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Preface 

These  three  lectures  were  delivered  before 
the  students  of  the  Medico-Chirurgical  College. 
Owing  to  the  many  requests  for  several  parts 
of  our  various  publications  of  the  work  done 
in  the  laboratory  I  have  thought  it  best  to 
incorporate  the  results  in  a  general  review  of 
the  internal  secretions.  While  many  state- 
ments are  contradictory,  yet  I  have  included 
them,  as  the  whole  subject  is  in  a  stage  of  flux 
and  reflux.  "Dire  n'est  rien;  faire  est  tout" — 
Renan.  Isaac  Ott. 

Sept.  28,  igio. 


in  the  laboratory  of  our  college.  It  was  the 
genial  Franco-American  physiologist,  Brown- 
Sequard,  who  in  1856  first  stated  that  the  adrenals 
when  removed  caused  the  death  of  the  animal. 
This  was  the  commencement  of  the  discoveries 
about  glands  with  an  internal  secretion. 

I  was  the  first  to  state,  in  the  Medical  Bulletin, 
1897,  that  "the  adrenals  enlarged  the  lumen 
of  the  intestine  at  the  moment  of  the  injection 
of  the  filtrate.  When  the  arterial  tension  is 
mounting  the  intestine  is  relaxing." 

This  property  of  the  adrenal  is  of  value  in 
intestinal  hemorrhage  of  typhoid  fever  in 
slowing  the  peristalsis.  In  the  same  paper  I 
showed  that  the  spleen  had  a  most  marked 
effect  in  exciting  peristaltic  movements.  I  have 
also  shown  in  the  laboratory  that  iodothyrin 
excites  peristalsis  and  explains  the  diarrhea 
in  exophthalmic  goitre,  where  we  usually  have 
a  hyperthyroidism.  We  also  found  that  the 
mammary,  prostate  and  spermin  were  power- 
ful excitants  of  uterine  contraction. 

The  parathyroids  were  first  discovered  by 
Sandstroem,  a  Swedish  anatomist,  in  1880. 
They  are  often  called  by  the  Germans,  epithelial 
bodies  (Epithelkoerper). 

Parathyroids,  Position  of. — In  the  cat  the 
parathyroids  are  very  regularly  four  in  number, 
two  on  each  lobe;  an  external  one  more  or  less 
free  ui!)on  the  external  surface  of  the  thyroid, 
and  an  internal  one  embedded  in  the  substance 
of  the  lobe  nearer  to  the  internal  than  the  ex- 


ternal  surface  of  the  thyroid,  and  always  smaller 
than  the  external.     From  their  anatomical  posi- 
tion  the   cat   is    the   most   suitable   animal  for 
parathyroidectomy.     In    color    and    size     they, 
resemble  in  the  cat  miliary  tubercles. 

The  rabbit  has  two  thyroid  lobes  connected 
by  an  isthmus.  In  each  lobe  is  embedded  a 
parathyroid.  Two  additional  parathyroids,  one 
on  each  side,  lie  distinct  from  the  thyroid, 
usually  at  some  distance  from  it.  He  has  four 
parathyroids. 

In  the  dog  there  are  four  parathyroids,  but 
the  external  pair  are  usually  embedded  in  the 
thyroid.  The  internal  parathyroids  are  rarely 
seen  exposed  upon  the  internal  surface  of  the 
thyroid. 

Guinea  Pig. — The  thyroids  usually  consist  of 
two  separate  and  distinct  lobes,  with  occasion- 
ally an  isthmus  uniting  the  lower  ends  of  the 
lobes.  The  number  and  position  of  the  para- 
thyroids is  variable,  more  so  than  in  any  other 
animal.  Each  lobe  of  the  thyroid  contains  a 
parathyroid  embedded  more  or  less  in  its  tissue; 
besides  these,  two  additional  parathyroids  on 
each  side  separated  from  the  thyroid  and  varia- 
ble in  position  in  the  levels  of  the  thyroids. 
He  has  four  parathyroids. 

Rats. — The  thyroid  consists  of  two  lobes 
united  by  an  isthmus,  one  parathyroid  to  each 
lobe,  lying  on  the  external  surface.  It  is  easily 
accessible  and  can  be  readily  cauterized. 


8 


In  the  monkey  there  are  four  parathyroids, 
always  embedded  in  the  substance  of  the  thyroid, 
two  in  each  lobe. 

In  man,  the  parathyroids  are  three  or  four 
in  number,  two  on  each  side  in  front  of  the 
vertebral  column  just  behind  the  rear  margins 
of  the  lateral  lobes  of  the  thyroid  gland.  The 
inferior  thyroid  artery  is  in  close  relation  with 
them.  A  small  grain  of  Indian  corn  repre- 
sents their  size  and  shape.  Their  color  is  red- 
dish yellow  or  reddish  brown  (Fig.   i). 


Fig.    1. — The  Four  Parathyroids  in  Man — Posterior  View 
(Zuckerkandl). 

Gilbride,  in  man,  found  that  the  most  common 
site  of  the  parathyroids  is  in  the  region  of  the 
inferior  poles  of  the  thyroid  gland;  the  superior 


or  external  glands  are  behind  and  close  to  the 
inferior  border  of  the  lateral  lobes  and  in  close 
proximity  to  the  inferior  thyroid  artery,  the 
inferior  or  internal  glands  lying  posterior  and 
below  the  superior  glands,  nearer  the  median 
line  or  below  the  thyroid  and  resting  on  the 
anterior  and  lateral  surface  of  the  trachea. 

W.  Berkeley,  in  125  autopsies,  occasionally 
found  as  many  as  five  or  six,  often  only  two  or 
three,  but  always  one,  parathyroid. 

Proportion  of  Parathyroid  to  That  of  the  Thy- 
roid.— Thyroid  tablets  of  commerce  are  chiefly 
from  the  glands  of  the  lamb.  The  fresh  thyroids 
of  six  mature  lambs  weighed  24.7  grams  (dried 
8.4  grams),  while  twelve  external  parathyroids, 
fresh,  weighed  0.23  gram  (dried  0.09  gram). 
In  feeding  with  thyroid  tablets  the  parathyroids 
play  an  exceedingly  small  part  in  the  medica- 
tion. 

Histology. — These  glands  are  rich  in  cellular 
elements  and  enclosed  by  a  delicate  capsule 
of  connective  tissue.  In  the  parathyroid,  trabec- 
ulae  run  from  the  deep  surface  of  the  enveloping 
capsule,  branch  and  unite  to  divide  the  interior 
of  the  gland  into  polygonal  compartments. 
The  cells  are  small,  with  a  large  round  nucleus. 
The  amount  of  protoplasm  in  the  cell  is  small. 
The  cells  of  the  parathyroid  are  in  structure 
very  different  from  those  of  the  thyroid.  The 
cells  are  of  two  types,  the  chief  and  oxyphile, 
which  are  considered  by  Forsythe  to  repre- 
sent two  stages  in  the  activity  of  one  kind  of 


lO 

cell.  In  repose,  the  clear  protoplasm  of  the 
chief  cells  are  filled  with  oxyphile  granules 
which  are  subsequently  extruded,  and  run  to- 
gether to  form  drops  of  colloid  material  which 
enters  the  blood  via  the  lymphatics. 

In  the  parathyroids  the  masses  of  polyhedral 
cells  are  in  varying  stages  of  active  secretion; 
often,  however,  a  drop  of  the  colloid  secretion 
forces  the  cells  apart.  The  formation  of  vesicles 
in  the  isolated  parathyroid  is  quite  common 
in  the  glands  of  man. 

Morphology. — Three  diverticula  form  the  thy- 
roid, a  median  one  growing  from  the  second 
visceral  arch  and  which  moves  to  a  pretracheal 
position,  where  it  is  connected  with  the  lateral 
thyroid  buds  which  develop  from  the  dorsal 
wall  of  the  fourth  inner  pharyngeal  cleft. 

Parathyroids  are  thickenings  of  the  epithelium 
on  the  dorsal  aspect  of  the  third  and  fourth 
visceral  clefts.  The  thymus  arises  as  a  pair 
of  outgrowths  from  the  epithelium  of  the  third 
cleft. 

Chemistry  of  the  Parathyroids. — The  colloid 
material  secreted  by  the  parathyroid  is  now 
conceded  not  to  contain  iodine.  Glycogen  is 
found  in  abundance. 

Blood  Supply. — The  parathyroids  receive  their 
blood  supply  usually  from  the  inferior  thyroid 
artery.  Nate  Ginsburg  has  shown  that  one  of 
the  superior  parathyroids  derives  its  blood 
supply  from  the  superior  parathyroid  artery 
instead    of    from    the    inferior    thyroid    artery. 


II 

Ginsburg  also  found  that  there  is  an  anastomosis 
between  the  parathyroid  arteries  on  one  side 
with  those  of  the  other,  so  if  one  of  the  inferior 
or  superior  thyroid  arteries  is  intact  the  blood 
supply  not  only  of  the  parathyroid  bodies  of 
one  side,  but  those  on  the  other,  are  preserved. 

Parathyroids  in  Thymus. — Erdheim  found  small 
accessory  parathyroid  glandules  in  the  thymus. 
This  has  also  been  seen  by  Pepere  in  rabbits 
and  in  man.  Harvier  and  MoreP  found  in  half 
of  the  cases  a  group  of  parathyroids  in  the  cat, 
chiefly  in  the  cervical  lobes.  They  found  that 
tetany  did  not  ensue  unless  these  thymic  para- 
thyroids were  also  removed.  Dr.  Scott  and  I 
have  frequently  noted  and  removed  the  thymic 
parathyroids. 

Changes  in  Parathyroids  after  Removal  of 
Thyroids. — When  the  thyroids  were  removed 
it  was  found,  by  Vincent  and  Jolly,  that  the 
parathyroid  tissue  approximates  in  appearance 
to  ordinary  thyroid  tissue.  There  is,  however, 
no  hypertrophy  of  the  tissues  of  the  parathyroids. 

Walter  Edmunds^  has  shown  by  experiments 
upon  dogs  that  the  parathyroids  even  when  left 
in  animals  with  great  thyroid  insuflEiciency  do 
not  change  into  thyroid  proper. 

What  is  Tetany? — This  name  "tetanie"  was 
first  used  by  Lucien  Vavirsort  in  1852.  It  is 
not  a  distinct  disease,  but  a  symptom-complex. 
It  consists  of  spontaneous  intermittent  muscular 
contractions,  attended  with  decreasing  strength 

1  Comptes  Rendus  de  la  Biologic,  May,  1909,  p.  837. 

2  Journal  of  Pathology  and  Bacteriology,  1910,  p.  288. 


12 

until  death  ensues.  There  is  also  a  spastic, 
tottering  gait,  tachycardia,  dyspnea,  rapid 
emaciation  and  psychical  depression.  It  is  as- 
sociated with  hypoparathyroidism. 

When  all  the  parathyroids  are  removed  there 
is  partial  paralysis,  especially  of  the  extensors; 
trembling  in  all  the  muscles,  followed  by  a  series 
of  convulsive  attacks,  with  loss  of  appetite; 
there  is  often  vomiting  and  dyspnea,  which 
is  replaced  by  polypnea  during  the  convul- 
sive attack.  The  temperature  rises  during  the 
convulsions,  which  fact  we  have  often  observed. 
This  tetany  begins  in  twenty-four  to  forty - 
eight  hours  after  the  operation  in  the  dog  and 
cat.  The  dog  generally  dies  from  the  second 
to  the  fifth  day  in  convulsions.  Robert  Quest, 
in  1905,  analyzed  the  brains  of  three  infants 
dead  by  tetany  and  found  the  amount  of  cal- 
cium to  be  small.  There  was  also  a  change 
in  the  proportion  between  the  amount  of  sodium 
to  that  of  calcium. 

Oddo  and  Sarles  found  the  urine  in  the  tetany 
of  infants  to  have  an  exaggerated  amount  of 
calcium  phosphates.  They  explained  the  cause 
of  tetany  to  be  due  to  loss  of  calcium  salts. 
Silvestri  (1906)  held  that  tetany  and  eclampsia 
could  be  explained  by  a  diminution  of  the  cal- 
cium in  the  organism. 

Netter  cured  three  cases  of  tetany  in  infants 
with  calcium  chloride  by  the  mouth.  Mac- 
Callum   and   Voegtlin  confirmed   the   results  of 


13 

Quest  as  to  the  lessened  amount  of  calcium  in 
the  brain.  They  also  confirmed  the  results 
of  Oddo  and  Sarles  that  there  was  an  increased 
excretion  of  calcium  in  the  urine.  MacCallum 
and  Voegtlin  also  found  the  calcium  content 
in  the  muscles  and  blood  to  be  one-half  the  usual 
amount.  Halstead  has  cured  tetany  in  man, 
due  to  the  removal  of  the  parathyroids  in  opera- 
tions on  the  thyroid,  by  calcium. 

MacCallum  and  Voegtlin  arrested  tetany  for 
twenty-fours  hours  in  dogs  when  seven  grains 
of  calcium  lactate  were  given  by  the  vein.  Beebe 
has  shown  that  injection  of  parathyroid  ex- 
tract causes  the  symptoms  of  tetany  to  vanish 
for  a  time,  but  death  finally  ensued,  just  as  it 
did  in  animals  after  the  use  of  calcium  lactate. 

Quantity  of  Calcium. — Parhon,  Dumitresco 
and  Nissipesco^  found  that  in  proportion  to 
weight,  animals,  cats  chiefly  and  dogs,  the 
proportion  of  calcium  in  the  nerve  centers  was 
greater  after  thyroparathyroidectomy  than  in 
normal  animals.  They  do  not  confirm  Silvestri 
and  MacCallum's  results. 

Leopold  and  V.  Reuss^  in  rats  after  removal 
of  the  parathyroids  found  rather  an  increase 
of  calcium  in  the  body  when  compared  with 
noirmal  animals.  These  experiments  would 
rather  support  the  theory  of  Stoelzner,  that 
there  is  a  hypercalcification  which  causes  tetany. 

Quest    made    some     experiments    upon    dogs 

1  Compies  Rendus  de  la  Societe  de  Biologie,  1909.  May,  p.  792. 
-  Wiener  Klin.  Wochenschrift,  No.  35,  1908,  p.  1243. 


14 

by  subcutaneous  injection  of  calcium  chloride 
solution  to  produce  an  excess  of  calcium  in 
the  body.  He  never  observed  an  elevation  of 
the  electric  excitability  of  the  nerves.  The 
faradic  current  showed  a  prompt  depression 
of  irritability.^  These  experiments  tend  to  prove 
that  Stoltzner's  idea  that  an  excess  of  calcium 
causes  tetany  is  not  correct. 

Musser  and  Goodman^  studied  the  metab- 
olism of  a  case  of  surgical  or  post-operative 
tetany.  They  found  no  "diabetes  calcareus," 
but  a  marked  diminution  of  the  calcium  in 
the  urine.  They  found  no  relation  between 
the  amount  of  calcium  and  the  severity  of  the 
symptoms.  They  pertinently  ask:  If  tetany 
is  due  to  a  withdrawal  of  calcium,  why  should 
the  symptoms  persist  when  the  organism  is 
in  the  perpetual  condition  of  calcium  store? 
Leopold  and  Von  Reuss  suggest  that  the  poison 
which  normally  is  paralyzed  by  the  parathyroids 
is  able  to  precipitate  calcium  and  leads  to  the 
deprivation  of  the  organism  of  active  calcium 
in  a  physiological  sense.  This  might  explain 
that  with  normal  or  increased  total  calcium 
there    could    be    a    poverty    in '  active    calcium. 

Musser  and  Goodman  found  a  high  percentage 
of  ammonia  in  the  urine,  it  never  falling  below 
5  per  cent.  This  coefficient  of  ammonia  bore 
a  distinct  relation  to  tetany.  They  practically 
found  that .  when  rigidity  or  some  distress  ref- 

'  Berliner  Klinische  W ochenschrifi,   1910,  p.  1074. 

-  University  of  Penna.  Medical  Bulletin,  p.  90,  May,  1909. 


15 

erable  to  the  tetany  was  complained  of,  the 
ammonia  percentage  was  raised.  They  are 
of  the  opinion  that  an  acidosis  may  be  the  under- 
lying feature  of  surgical  tetany. 

MacCallum  and  Voegtlin  have  discovered 
in  parathyroidectomized  animals:  (i)  a  marked 
reduction  in  the  calcium  content  of  the  tissues, 
especially  of  the  blood  and  brain;  (2)  an  in- 
creased output  of  calcium  in  the  urine  and  feces 
on  the  development  of  tetany;  (3)  an  increased 
output  of  nitrogen  in  the  urine;  (4)  an  increased 
output  of  ammonia  in  the  urine,  with  an  in- 
creased ammonia  ratio  in  the  urine;  and  (5) 
an  increased  amount  of  ammonia  in  the  blood. 

Jean  V.  Cooke^  found  in  dogs  dying  from 
parathyroid  tetany  a  slightly  greater  amount 
of  calcium  in  the  brain  than  in  the  brain  of 
normal  dogs,  which  indicates  that  a  decreased 
calcium  content  of  the  brain  is  not  constant 
in  tetany.  After  removal  of  the  parathyroids, 
with  the  animal  fasting,  the  elimination  in  urine 
of  magnesium  is  greatly  increased,  while  that 
of  calcium  remains  unchanged.  The  augmenta- 
tion of  magnesium  begins  before  tetany  is  ob- 
served. It  is  suggested  that  tetany  represents 
a  condition  of  altered  salt  equilibrium  in  the 
nerve  cells  brought  about  by  a  disturbance  in 
the  catalytic  processes  of  the  body  which  in- 
creases the  acid  factors. 

Walter  Edmunds^  found  in  animals,  if  a  large 

'  Proceedings  of  Society  for  Experimental  Biology  and  Medicine, 
1909.  p.  13. 

^  Journal  of  Pathology  and  Bacteriology,  1910,  p.  290. 


.16 

amount  of  calcium  was  given  or  mainly  fed  on 
milk  previous  to  the  operation,  that  after  a  total 
thyroidectomy  which  includes  the  parathyroids 
the  symptoms  ensuing  are  removed  or  tem- 
porarily mitigated.  The  calcium  and  milk  was 
continued  after  the  operation. 

Poison  in  the  Blood  of  Animals  in  Tetany. — 
Pfeififer  and  Mayer  found  in  the  sera  of  six  out 
of  seventeen  dogs,  which  had  tetany  after  re- 
moval of  the  parathyroids,  a  toxic  principle. 
This    was    shown    by    experiments    upon    mice. 

Berkeley  and  Beebe  regard  tetany  to  be  due 
to  a  metabolic  poison:  (i)  the  symptoms  have 
a  central  origin;  (2)  the  symptoms  are  shown 
best  in  young  animals  and  are  more  severe  if 
the  animal  is  kept  on  a  meat  diet;  (3)  the  symp- 
toms have  a  close  relation  to  certain  chemical 
conditions  which  are  accompanied  by  severe 
nutritional  disturbances;  (4)  gastric  tetany  is 
accompanied  by  severe  metabolic  disturbances, 
it  has  similar  symptoms  and  is  promptly  re- 
lieved by  intravenous  injection  of  calcium  and 
by  parathyroid  and  nucleoproteid ;  (5)  bleed- 
ing followed  by  intravenous  infusion  relieves 
the  animal,  a  procedure  well  suited  to  free  the 
body  from  a  circulating  poison;  (6)  symptoms 
are  promptly  relieved  by  the  injection  of  fresh 
parathyroid  nucleoproteid;  (7)  injections  of 
known  simple  poisons,  such  as  ammonia  and 
xanthin,  produce  symptoms  which  can  be 
promptly  relieved  by  injections  of  calcium  or 
strontium    salts    similar    to    the    relief    obtained 


17 

by  the  same  means  in  tetany;  (8)  parathyroid 
tetany  has  a  deranged  metabolism  accompanied 
by  a  large  increase  in  the  excretion  of  ammonia. 

Meljnikow/  in  tetany  of  rabbits  after  re- 
moval of  parathyroids,  found  that  injections 
of  calcium  acetate  quickly  improved  the  ani- 
mals, but  it  was  quite  temporary.  He  states 
that  the  parathyroids  have  a  specific  histo- 
logical structure  which  is  not  converted  into 
thyroid  tissue.  Goitre  degeneration  of  the  thy- 
roid has  but  little  effect  upon  the  parathyroids. 
There  is  some  regressive  change,  probably  due 
to  mechanical  pressure  from  the  enlarged  thy- 
roid, and  not  to  any  physiological  connection 
with  the  thyroid. 

Beebe  found  that  strontium  acted  equally 
well  as  calcium  in  relieving  tetany.  Barium 
also  relieves  tetany.  These  facts  indicate  that 
calcium  loss  is  only  a  part  of  the  factors  in  the 
course  of  tetany. 

Bleeding  cures  tetany,  but  it  can  not  do  it 
by  loss  of  calcium,  as  this  operation  diminishes 
this  element  more.  It  is  not  likely  in  forty- 
eight  hours  after  the  operation  that  in  the  onset 
of  tetany  the  hypocalcification  is  so  great  as 
to  cause  the  disease,  for  plenty  of  calcium  can 
come  from  the  store-house  in  the  bones. 

Magnesium  also  relieves  tetany,  according 
to  MacCallum  and  Beebe.  Neither  barium 
nor  magnesium  should  be  used,  as  they  are 
toxic  to   the  heart.     Beebe  found  parathyroid 

1  Wiener  Klinische  Wochensckrifi,  1910,  p.  410. 


nucleoproteid  to  relieve  tetany.  The  globulin 
in  parathyroids  has  no  effect  on  tetany.  The 
nucleoproteid  will  relieve  tetany  if  given  by 
the  mouth,  but  is  much  more  quickly  and  cer- 
tainly effective  when  given  subcutaneously  or 
intraperitoneally. 

Berkeley  and  Beebe  are  inclined  to  believe 
that  the  parathyroids  are  chiefly  concerned  in 
furnishing  enzymes,  which  are  of  prime  im- 
portance in  the  intermediary  metabolism  of 
nitrogen.  They  do  not  believe  that  the  ab- 
normal secretion  of  calcium  is  the  cause  of 
tetany,  but  a  deranged  metabolism  giving  rise 
to  an  active  poison. 

Clara  Jacobson  finds  in  the  blood  of  para- 
thyroidectomized  animals  an  increase  of  am- 
monia and  she  believes  it  is  directly  responsible 
for  the  tetany,  as  the  concentration  of  ammonia 
in  the  blood  of  the  parathyroidectomized  cats 
and  dogs  is  sufficient  to  cause  tetany,  tremors, 
and  depression  in  the  normal  animal.  Nor- 
mally in  cats  it  is  1.57  milligrams  per  100  cc, 
but  in  parathyroidectomized  animals  it  is 
on  an  average  of  6  animals  2.53.^ 

Our  experiments  were  made  upon  sixty  cats 
and  two  dogs.  One  hundred  and  thirty- three 
observations  were  made  on  these  sixty-two 
animals.  The  cats  were  first  etherized,  then 
the  parathyroids  removed  under  antiseptic  pre- 
cautions.    The    thymus    was    always    examined 

1  Proceedings    of   Society   for   Experimental   Biology   and   Medi- 
cim.  Vol.  VIII,  No.  4.  p.  124. 


19 

for  parathyroids.  The  cat  has  usually  four 
parathyroids,  but  more  may  exist.  In  young 
cats  the  parathyroids  have  a  looser  anatomical 
relation  to  the  thyroid  than  later  in  life.  In 
many  cases  some  of  the  thyroid  was  removed 
in  the  desire  to  obtain  all  the  parathyroids, 
but  enough  thyroid  was  left  to  maintain  its 
functions.  When  removal  in  part  of  the  para- 
thyroids was  ineffectual  to  produce  a  tetany, 
then  the  thyroid  was  also  removed,  and  we 
always  found  it  contained  a  parathyroid  larger 
than  the  normal.  In  cats,  when  all  the  para- 
thyroids were  removed  symptoms  of  tetany 
came  on  in  about  forty-eight  hours  as  a  rule. 
The  first  symptoms  were  a  slowness  in  move- 
•ment  and  a  state  of  apathy.  The  animals 
were  disposed  to  remain  in  one  place.  First, 
as  a  rule,  was  developed  a  lifting  of  the  pos- 
terior extremities  and  sometimes  of  the  an- 
terior, as  though  the  animal  had  been  stepping 
in  water.  The  posterior  extremities  were  stiff- 
like in  movement  and  spread  apart  in  their 
gait.  Then  trembling  ensued  in  the  extrem- 
ities, followed  by  convulsions  of  the  whole 
body.  In  the  convulsive  state  the  animal 
usually  made  loud  cries  before  and  after  the 
convulsion.  Conjunctivitis  was  frequently  noted 
in  the  tetania  parathyreopriva.  The  sense  of 
hearing,  sight,  smell,  and  taste  remained.  They 
did  not  respond  to  petting.  They  also  had  the 
projecting  abdomen  noted  by  Hagenbach. 

In  some   old   cats   some  time   after  removal 


20 

of  parathyroids  and  thyroids  and  careful  ex- 
amination of  the  thymus,  no  tetany  ensued 
for  two  weeks.  Now,  Bell  and  Martin  have, 
shown  that  pituitary  increases  the  calcium 
content  of  the  blood.  Hence,  it  is  probable 
that  the  well-developed  pituitary  of  old  animals 
was  sufficient  to  delay  the  appearance  of  tetany, 
although  the  animals  were  kept  on  a  meat  diet, 
which  favors  tetany.  We  injected  subcutane- 
ously  in  animals  with  tetany  about  ten  to  twenty 
grains  of  pituitary  extract,  rubbed  up  with  dis- 
tilled water.  Then  in  about  three  hours  the 
vacillating,  spastic  gait  disappeared,  the  tremor 
was  replaced  by  steadiness,  and  the  lifting  of 
the  feet  as  though  wet  with  water  disappeared. 
The  head,  which  usually  hung  down,  was  ele- 
vated, and  the  whole  bearing  of  the  animal 
was  changed.  This  continued  for  about  twenty- 
four  hours,  when  tetany  reappeared.  In  no 
case  were  we  able  to  prevent  death  by  repeated 
injection  of  the  pituitary.  We  also  injected 
pituitary  by  the  vein,  but  the  best  results  were  ob- 
tained by  subcutaneous  injections.  That  neither 
calcium  nor  its  combination  with  other  salts 
was  concerned  in  the  action  of  the  pituitary 
was  proved  by.  the  fact  that  incineration  of 
the  pituitary  extract  and  the  injection  of  the 
ash  was  not  followed  by  any  curative  effect. 
The  extract  was  subjected  to  intense  heat  in 
a  capsule  for  a  couple  of  hours,  then  the  re- 
maining salts  were  dissolved  in  distilled  water 
and  injected  subcutaneously  and  by  the  vein. 


21 

All  our  observations  show  that  it  is  an  organic 
body  in  the  pituitary  which  abates  the  tetany. 
We  also  tried  pituitrin,  an  acidulated  extract 
of  the  infundibular  part  of  the  pituitary.  It 
was  used  subcutaneously  in  doses  of  4  cc.  up 
to  28  cc.  It  acts  rapidly  in  the  relief  of  tetany, 
but  the  action  is  much  more  fugitive  than  the 
pituitary  extract.  Pituitary  extract  by  the 
jugular  is   not   as   effective   as   subcutaneously. 

Adrenalin  was  given  by  the  jugular,  in  the 
cat,  and  some  improvement  was  noted.  Lowen- 
thal  and  Wiebrecht  saw  a  good  effect  in  human 
tetany  by  adrenal  extract. 

lodothyrin  was  also  given  by  the  jugular,  and 
it  had  a  quieting"  action  upon  the  tremor. 

Mammary  gland,  thymus,  testicle,  prostate, 
spleen,  spinal  cord  (all  rubbed  up  with  distilled 
water),  and  Poehl's  spermin  had  no  effect  upon 
tetany;  they  were  all  given  subcutaneously. 
Pancreas  had  a  quieting  effect  in  seven  cases 
out  of  ten. 

As  to  the  comparative  value  of  pituitary 
extract  and  calcium  lactate,  our  experiments 
did  not  show  any  particular  difference.  The 
intravenous  injection  of  calcium  lactate  passed 
off  quickly,  while  the  subcutaneous  effect  of 
pituitary  came  on  slower  and  continued  longer. 

Pituitrin  did  not  have  the  permanent  effect 
that  the  gland  substance  did.  Evidently  in 
tetany  the  gland  itself  should  be  used,  as  there 
is  something  wanting  in  the  pituitrin.  The 
"Vaporole"    Extract    of    Infundibulum  (i  cc.) 


22 

2o%  (Burroughs  Wellcome  &  Co.)  may  be 
the  best  to  use.  It  is  inferable  that  the  in- 
fundibular lobe  is  the  active  part  of  the  gland 
in  antagonizing  the  tetany  after  the  removal 
of  the  parathyroids. 

As  to  the  cause  of  tetany,  we  have  two  theories, 
one  of  hypocalcification,  held  by  Silvestri, 
Netter,  Quest  and  MacCallum;  the  other,  that 
the  removal  of  the  parathyroids  leaves  a  poison 
in  the  blood  (Pfeiffer  and  Mayer),  or,  according 
to  Berkeley  and  Beebe,  it  is  a  poison  generated 
in  proteid  metabolism. 

Beebe's  experiments  showing  that  strontium 
will  relieve  tetany  quite  as  well  as  calcium 
indicate  that  hypo-calcification  is  not  the  whole 
cause   of   tetany,    but   only   an   epiphenomenon. 

Our  experiments  show  that: 

(i)  Removal  of  the  parathyroids  alone  causes 
tetany. 

(2)  Pituitary  extract  will  temporarily  cure 
tetany. 

(3)  Between  the  parathyroids  and  the  pitui- 
tary there  is  a  co-operative  action. 

(4)  The  infundibular  lobe  contains  the  active 
principle. 

(5)  Tetany  is  not  due  to  want  of  calcium, 
but  to  a  poison  in  the  blood. 

The  nucleoproteid^  (S.  P.  Beebe's  method)^ 
was  used  in  part  of  the  experiments  upon  the 
intestine,  uterus  and  kidney.     The  gland  itself 

1  Thanks  to  kindness  of  Dr.  W.  N.  Berkeley,  of  New  York. 
^  The  Old  Dominion  Jo%irn<ll  of  Medicine  and  Surgery,  April, 
1909.  p.  231. 


■\rf' 


lines  represent  drops  of  urini 


■/■/v■^A"■/.'^f^'''■,/-V 


'  II  1  V  fi  11  "  n H-  If  'fi'  V  1,1  ,1  M  ','  1,1  ',0  V  ' 


v\^/\^^v\'v^l^/V\^^A;Vvv^^,v^/'v^^V■ 


—Effect  of  nucleoproteid  (3   gtts)  on  the  t 


t  does  not  alter  the  pulse  rate.     The  vertical  lines  represent  drops  of  urine  noted  witli  an  elect 


23 

was  also  used.  It  was  rubbed  up  with  distilled 
water,  heated  and  filtered.  The  intestine  and 
uterine  tissue  were  excised  and  placed  in  Ringer's 
solution  and  attached  to  a  Porter  heart-lever. 
The  oxygen  was  bubbling  through  the  solu- 
tion at  about  the  rate  of  200  per  minute.  The 
temperature  of  the  Ringer  solution  was  37°  C. 
It  is  the  method  of  Magnus.  The  nucleoproteid 
increased  the  tonus  and  extent  of  the  contrac- 
tions of  the  intestine  (Fig.  2).  It  also  increased 
the  force  of  the  contractions  of  the  uterine 
tissue  (Fig.  3). 

Studies  were  also  made  upon  the  circulation. 
The  arterial  pressure  after  injection  per  jugular 
of  three  drops  of  nucleoproteid  rose  slightly 
and  then  fell.  Doses  of  ten  to  fifteen  drops 
caused  an  immediate  fall  of  pressure.  The 
pulse    rate    was    not    changed    much    (Fig.    4). 

In  the  cat  Vg  grain  of  the  powdered 
parathyroid  per  jugular  in  a  watery  solution 
momentarily  depressed  the  pulse  rate  and  later 
increased  it  above  normal.  The  blood  pressure 
at  the  time  of  the  injection  fell  greatly,  but 
afterwards   rose   again   but   seldom    to   normal. 

Respiration.- — One-eighth  grain  of  the  para- 
thyroid per  jugular  decreased  the  rate  of 
respiration.  The  nucleoproteid  by  the  jugular 
increased  it. 

Temperature. — -Large  doses  of  the  nucleo- 
proteid reduced  the  temperature  in  rabbits 
which  were  permitted  to  run  about  the  labora- 
tory. 


24 

Diuresis. — Our  experiments  were  made  mainly 
upon  cats;  a  few  rabbits  were  also  used.  The 
animal  was  bound  down,  given  5  cc.  of  paralde- 
hyde by  the  mouth,  then  chloroform  was  given. 
The  abdomen  was  opened  in  the  median  line 
over  the  bladder,  the  bladder  drawn  out  and 
an  incision  made  into  it.  A  funnel-shaped 
glass  tube  with  a  flange  was  inserted  into  the 
bladder  and  walls  of  this  viscus  tied  about  the 
flange.  Then  the  bladder  was  filled  with  the 
urine  previously  obtained  from  the  bladder. 
If  this  was  not  sufficient  to  fill  the  bladder, 
then  Ringer's  solution  was  added.  By  means 
of  a  piece  of  rubber  tubing  attached  to  the 
funnel-shaped  tube  the  urine  was  .  permitted 
to  drop  into  the  capsule.  This  was  done  for 
about  fifteen  minutes,  when  each  drop  of  urine 
was  noted  on  the  smoked  drum  with  an  elec- 
tric marker.  Then  the  extract  or  powdered 
gland  was  rubbed  up  with  distilled  water,  fil- 
tered and  injected  into  the  jugular.  The  drops 
of  urine  were  again  noted.  The  bladder  was 
kept  moist  with  absorbent  cotton  wet  with 
Ringer's  solution.  The  blood  pressure  was  fre- 
quently noted  at  the  time  the  urine  was  drop- 
ping. 

We  found  that  the  parathyroid  nucleoproteid 
in  some  cases  increased  diuresis  in  a  half- hour 
tenfold  (Fig.  5).  The  pancreas,  thymus  and 
extract  of  the  renal  cortex  were  also  found  by 
us  to  be  excitants  of  diuresis. 

This     diuretic    action    by     the    parathyroids 


Pjq    5 »f  urine.        Normally  it  was  4  drops  in 


Fig.  5. — One  drop  of  nucleoproteid  increased  urinary  secretion  tenlold  between   ] 


ical  lines  indicate  drops  of  urine.        Normally  it  was  4  dre 


25 

is  greater  than  that  of  any  of  the  glandular 
extracts,  not  excepting  pituitrin.  It  is  a  di- 
rect action  upon  the  glandular  epithelium, 
as  it  occurs  in  experiments  where  the  blood- 
pressure  is  falling  from  the  beginning. 

The  small  size  of  the  four  parathyroids 
in  the  cat  must  secrete  a  very  minute  quantity 
of  material  to  act  upon  the  kidneys.  Accord- 
ing to  the  size  of  the  dose,  it  is  probably  one 
of  the  strongest  of  all'  diuretics.  Hence  the 
parathyroids,  in  addition  to  the  maintenance 
of  the  reflex  activity  of  the  nerve  cells,  also 
have  another  great  and  important  function, 
the  stimulation  of  the  renal  epithelium. 

Action  on  Pupil. — Meltzer^  was  first  in  show- 
ing that  adrenalin  dilated  the  pupil  wlien  locally 
applied  to  the  eye  of  a  rabbit  in  which  extirpa- 
tion of  the  superior  cervical  ganglion  had  been 
done  twenty-four  hours  previously.  It  had 
no  effect  on  the  normal  eye,  but  Schultz  has 
since  shown  that  large  doses  frequently  applied 
dilate  it  also.  Our  experiments  were  made 
•  upon  rabbits.  The  superior  cervical  ganglion 
was  excised  under  ether  and  next  day  the  nucleo- 
proteid  of  the  parathyroids  dropped  into  both 
eyes.  The  intensity  of  the  light  was  regulated 
so  as  to  be  about  the  same.  The  rabbit  was 
placed  upon  a  table  and  permitted  to  run  over 
it.  The  diameter  of  the  pupil  was  measured 
with  a  pair  of  compasses.  On  the  normal 
eye  it  dilated  the  pupil;  on  the  eye  on  the  side 

1  Am.  Journal  of  Physiology,  Vol.  XI,  1904.  p.  28. 


26 


where  the  superior  cervical  ganglion  was  ex- 
cised it  at  first  contracted  and  then  dilated  the 
pupil. 

PATHOLOGY. 

Paralysis  Agitans. — Dr.  W.  N.  Berkeley,  of 
New"  York,  has  put  forth  a  theory,  also  inde- 
pendently propounded  by  Lundborg,  that  this 
disease  can  be  greatly  benefited  by  the  use 
of  the  parathyroids.  The  trembling,  rigidity, 
salivation  and  the  propulsive  movements  of 
animals  resemble  somewhat  the  symptoms  of 
paralysis  agitans.  Besides,  cases  of  myxedema 
and  exophthalmic  goitre  are  sometimes  asso- 
ciated with  paralysis  agitans.  Here  the  para- 
thyroids may  be  involved.  On  post  mortem 
Berkeley  has  found  a  sclerosis  of  the  parathy- 
roids. Dr.  Camp  reported  two  cases  of  paralysis 
agitans  in  which  the  parathyroids  were  dis- 
eased. In  one  there  was  some  colloid  material, 
and  in  both  there  was  a  peculiar  infiltration 
with  fat,  especially  in  relation  to  the  blood 
vessels.  Dr.  Berkeley,  from  an  experience  cover- 
ing several  years,  has  arrived  at  the  conclusion 
that  nearl}^  all  the  patients  with  paralysis  agitans 
slowly  respond  to  the  treatment  by  parathy- 
roids. In  25  per  cent,  of  the  cases  the  response 
is  temporary  and  imperfect.  Seventy-five  per 
cent,  showed  progressive  benefit  during  the 
entire  period:  the  rigidity  diminished,  the  pain 
lessened,  salivation  was  cured,  the  shaking  dimin- 
ished or  was  cured,  voluntary  control  of  the 
muscles  greatly  increased,  and  restlessness  and 


27 

insomnia  were  nearly  or  quite  abolished.  Berkeley 
states  that  these  glands  are  antispasmodic  in 
their  action,  and  may  be  of  service  in  a  number 
of  different  diseases. 

Krdheim,  in  1883,  found  in  a  case  of  paralysis 
agitans  a  hyperplasia;  the  oxyphile  cells  of 
the  parathyroids  were  unusually  enlarged. 

Roussy  and  Jean  Clunet^  in  four  cases  of 
paralysis  agitans  found  histological  evidence 
of  a  hyper-function  in  the  parathyroid  glands. 

MEDICAL   TETANY. 

Tetany  of  Gastric  Origin. — In  two  cases  of 
tetany  due  to  dilation  of  the  stomach,  and  one 
by  an  enteritis,  there  were  no  corresponding 
changes  in  the  parathyroid  sufficient  to  account 
for  the  tetany.  There  was  a  possible  insuffi- 
ciency of  secretion  by  the  glandules. 

MacCallum  (1905)  .  examined  the  parathy- 
roids in  an  old  man  dead  from  gastric  tetany, 
caused  by  pyloric  stenosis  and  gastric  ulcer. 
He  found  five  rather  large  parathyroids,  which 
showed  large  groups  of  eosinophile  cells  under- 
going mitosis  to  a  large  degree.  He  inferred 
a  hyperplasia  of  the  glandules.  He  thinks 
the  dilated  stomach  generated  a  poison  which 
the  parathyroid  secretion  neutralized.  But  as 
it  was  an  insufficient  neutralizer,  tetany  ensued 
on  account  of  the  excess  of  the  poison. 

Berkeley  reports  a  case  occurring  in  the  prac- 
tice of  Dr.  W.  B.  James  of  gastric  tetany  in  a 

1  Comptes    Rend2is    de    la   Societe     de     Biologie,    Vol.    LXVIII, 
p.  320,  1910. 


28 


man  35  years  old  who  had  extreme  dilatation 
of  the  stomach.  He  had  violent  symptoms, 
and  his  life  was  despaired  of.  Capsules  of 
parathyroid  improved  and  cured  him.  Dr. 
Kinnicutt  had  a  patient  with  gastric  tetany 
in  which  the  capsules  cured  the  tetany,  but  the 
patient  died.  He  had  extreme  dilatation  of 
the  stomach.  Calcium  lactate  given  by  Dr. 
Beebe  also  reduced  this  patient's  tetany. 

Tetany  of  Pregnancy. — Idiopathic  tetany  was 
first  described  in  1830,  by  Stringheim.  N. 
Weiss,  in  1880,  connected  tetany  with  thyroidec- 
tomy. It  has  been  found  that  in  animals  which 
have  two  of  the  parathyroids  removed,  not  all 
of  them,  that  at  the  end  of  pregnancy  tetany 
ensues.  After  the  delivery  the  tetany  disap- 
pears. At  the  end  of  a  second  pregnancy  tetany 
again  ensues.  Here  we  have  a  hypoparathy- 
roidism. These  facts  led  to  the  theory  that 
puerperal  eclampsia  is  due  to  deficiency  of 
secretion  by  the  parathyroid. 

Pepere  (1905)  had  four  cases  of  eclampsia, 
in  three  he  found  two  parathyroids  missing, 
and  in  one  he  discovered  a  severe  injury  of  one 
parathyroid  because  of  a  cystic  degeneration, 
while  the  other  three  were  intact. 

Zanfrognini  (1905)  found  in  a  case  of  eclampsia 
only  two  parathyroids  present,  and  no  trace  of 
hypertrophy  in  them.  He  also  (1905)  treated 
five  cases  of  eclampsia  with  the  parathyroidine 
of  Vassale,  when  the  convulsions  ceased,  albumen 


29 

disappeared  from  the  urine  and  the  pulse  was 
better. 

The  tetany  can  ensue  in  the  first  pregnancy, 
and  also  take  place  in  the  second  pregnancy, 
or  it  can  first  occur  in  later  pregnancies.  It 
may  take  place  in  the  first  month,  or  about  the 
sixth  month,  or  shortly  ante  partum.  Its  course 
is  inconstant.  Weiss  saw  in  the  fourth  month 
of  pregnancy  after  a  total  thyroidectomy  a 
tetany  which  towards  the  end  of  pregnancy 
stopped,  but  post  partum  again  returned.  Meinert 
(1889)  had  a  case  in  the  fourth  month  of  preg- 
nancy with  a  one-sided  thyroidectomy,  and 
tetany  ensued.  The  second  pregnancy  was 
free  from  tetany.  In  the  eleventh  pregnancy 
strong  tetany  ensued  about  the  eighth  month. 
Several  cases  are  recorded  similar  to  the  above 
by  Von  Kiselsberg,  Westphal,  Peham,  and 
Dienst. 

Tetany  of  Infants. — In  two  cases  of  tetany 
of  infants,  Erdheim  found  in  both  cases  a  hemor- 
rhage in  the  parathyroids. 

Haberfeld  has  found  that  the  parathyroids 
can  be  a  seat  of  hemorrhage  causing  a  hypo- 
plasia. It  is  in  the  parenchyma  of  the  gland 
that  the  lesion  is  seated.  He  found  in  many 
cases  of  tetany  in  children  that  the  parathy- 
roids were  the  seat  of  hemorrhage.^ 

SURGICAL  TETANY. 
Tetany  Due  to  Surgical  Procedures  in  Man. — 
In    1886    Billroth    did    a    total    thyroidectomy 

^Wiener  Klin.  Wochenschrift,  XXIII,  27,  p.  1017. 


30 

for  an  adenocarcinoma  of  the  thyroid,  and  a 
temporary  tetany  ensued.  In  1892  a  second 
operation  was  made  on  this  patient,  a  resection 
of  the  manubrium  sterni.  On  the  ninth  day 
after  the  operation  tetany  ensued  and  recurred 
often  in  the  following  years.  It  is  supposed 
that  the  first  operation  removed  only  part  of 
the  parathyroids,  while  the  second  operation 
injured  the  glandules  in  the  th3'mus,  as  there 
was  metastasis  in  the  neck  at  the  time  of  the 
second  operation.  Kocher  observed  a  tetany 
resulting  in  death,  after  ligature  of  four  of  the 
arteries  suppljdng  the  thyroid,  and  Kopp  also 
observed  tetany  after  ligature  of  two  and  three 
arteries  of  the  thyroid.  Dr.  J.  J.  Putnam,  of 
Boston,  in  a  case  of  post-operative  tetany, 
greatly  relieved  the  tetany  by  the  use  of  the 
parathyroid  capsules  of  Berkeley. 

Halstead  (1907),  of  Baltimore,  Pool  (1907), 
of  New  York,  and  Branham  (1908),  of  Texas 
have  reported  cases  of  tetany  after  thyroidec- 
tomy. Halstead's  case  was  greatly  relieved 
by  parathyroids. 

In  case  of  carcinoma  of  the  thyroid  the  whole 
gland  must  be  removed,  notwithstanding  the 
tetany,  as  it  can  be  alleviated  by  the  means 
already  specified.  The  great  number  of  opera- 
tions now  for  exophthalmic  goitre  and  goitre 
proper  make  surgical  tetany  an  important 
subject.  Patients  with  Graves'  disease  bear 
badly  the  loss  of  parathyroids. 

In  disease  of  the  thyroid  not  malignant  the 


31 

surgeon  must  not  only  leave  a  part  of  the  thyroid 
to  prevent  myxedema,  but  also  the  para- 
thyroids to  prevent  tetany.  Two  of  these 
bodies  in  man  are  extra-capsular  and  can  be 
avoided  in  the  operation.  If  all  the  para- 
thyroids are  removed,  then  transplantation  of 
these  bodies  must  be  attempted. 

Transplantation  of  Parathyroids  for  the  Cure 
of  Tetany. — Transplantation  does  not  succeed 
unless  some  of  the  parathyroids  have  been  pre- 
viously removed. 

Von  Eiselsberg,  in  1892,  transplanted  the 
parathyroids  successfully,  and  they  were  func- 
tionally active. 

Many  others  have  done  the  same.  W.  S. 
Halstead,^  of  Baltimore,  has  found  that  auto- 
transplantation  of  parathyroid  glandules  into 
the  thyroid  and  behind  the  rectus  abdominis 
muscle  has  been  successful  in  61  per  cent,  of 
cases  in  which  a  deficiency  greater  than  one- 
half  of  the  parathyroids  had  been  created. 
Isotransplantation  has  been  uniformly  success- 
ful. One  parathyroid  graft  may  suffice  to 
maintain  the  animal  in  good  health  and  spirits 
for  many  months. 

Danielsen^  relates  a  case  of  tetany  occurring 
on  the  sixth  day  after  a  thyroidectomy.  The 
transplants  from  two  other  parathyroids  which 
had  been  removed  and  placed  between  the 
fascia  and  the  peritoneum  cured  the  tetany. 

'  Journal  of  Experimental  Med.,  Vol,  XI,  No.  1,  p.  198. 
-  Muiichener  Medizinische  Wochenschrifi,   1910,  p.  973. 


32 

In  mild  cases  of  tetany  he  recommends  3 
grains  chloral  a  day,  and  protracted  warm  baths. 

Messrs.  Herman  and  Harvey^  have  made  a 
series  of  experiments  upon  dogs,  and  have  found 
that  auto-transplantations  are  more  successful 
than  iso-transplantations.  They  think  the  vis- 
ceral peritoneum  is  superior  to  the  spleen  as 
a  site  for  the  transplantation  of  parathyroid. 
They  also  show  that  isotransplantation  is  possi- 
ble. 

Schneider^  reports  a  case  of  sarcoma  of  the 
thyroid  and  parathyroids  whose  removal  was 
followed  by  severe  tetany.  Fresh  parathyroid 
substance  from  the  horse,  dried  and  powdered, 
was  given  and  he  says  that  a  specific  favorable 
effect  on  the  tetany  was  unmistakable.  The 
patient  was  a  woman  of  40.  She  succumbed, 
before  the  year  was  out,  to  the  progress  of  the 
malignant  disease. 

Tumors  of  Parathyroids. — Berard  and  Alamar- 
tine^  found  from  an  examination  of  the  para- 
thyroids a  case  of  tumor  of  one  parathyroid. 
From  the  records  they  have  assembled  twenty- 
nine  cases  of  tumor  of  the  parathyroid.  Of 
these  cases  three  were  malignant,  and  metastasis 
proved  fatal  after  removal  of  the  primary  tumor. 
In  twent5^-four  cases  the  tumor  was  formed 
solely  of  parathyroid  tissue,  while  in  five  there 
were   islands   of  thyroid   tissue.     Rapid  growth 

'  University  of  Penna.  Medical  Bulletin,  June,  1909,  p.   136. 
-  Jaurnal  of  Am.  Med.  Association,  1910,  p.  1912. 
3  Journal  Am.  Med.  Association,  1909,  p.  241. 


33  • 

of  a  tumor  in  a  parathyroid  indicates  malig- 
nancy. 

Changes  in  Teeth. — Erdheim  noted  not  only 
tetany  in  the  rat,  but  changes  in  the  teeth  with 
which  the  rat  gnaws.  The  enamel  on  the  anterior 
surface  of  the  teeth  becomes  opaque,  and  white 
spots  appear  in  it.  The  teeth  often  break  off 
in  the  alveolus.  This  happens  first  in  the  upper 
jaw,  then  in  the  lower.  The  microscopic  changes 
in  the  teeth  show  changes  first  in  the  dentine, 
then  in  the  enamel  and  its  epithelium.  There 
is  a  hypocalcification  in  the  dentine.  After 
the  fracture  of  the  teeth,  the  teeth  in  the  antago- 
nizing jaw  attain  great  length.  Erdheim  has 
also  noted  changes  in  the  lens,  resulting  in 
cataract.  In  four  cases  of  puerperal  eclampsia, 
there  was  hyperemia  of  the  parathyroids  and 
in  two  one  of  the  parathyroids  had  a  small 
circumscribed  spot,  an  injury  of  the  parenchyma, 
and  in  one  "of  these  two  cases  a  small  hemor- 
rhage into  the  glands. 

Erdheim  believes  that  there  is  a  connection 
between  osteomalacia  and  parathyroid  insufii- 
ciency,  the  direct  result  of  the  involvement  of 
calcium  metaboUsm. 

Osteomalacia  puerperalis,  according  to  Erd- 
heim, is  associated  with  disease  of  the  epithelial 
bodies.  Here  he  found  often  hypertrophy  of 
the  parathyroids  and  consequently  a  hyperpara- 
thyroidism. 

In  congenital  cretins,  where  the  thyroid  is 
absent,    the    symptoms    of    cretinism    continue 


34 

although  all  the  parathyroids  are  present. 
The  growth  of  the  bones  in  these  cases  is  re- 
tarded; the  presence  of  the  epithelial  bodies 
does  not  prevent  it.  They  are  not  converted 
into  thyroid  tissue,  as  held  by  some  English 
physiologists. 

Roussy  and  Clunet^  ha\e  studied  the  thyro- 
parathyroid  apparatus  in  two  congenital  cases 
of  myxedema  aged  28  years.  They  found  the 
thyroid  reduced  to  the  volume  of  a  grain  of 
wheat  and  it  had  an  embryonic  histological 
structure  comparable  to  that  met  with  in  the 
first  months  of  fetal  life.  The  parathyroids 
were  well  developed,  the  volume  of  each  one 
exceeded  by  30  to  40  times  that  of  the  thyroid; 
their  structure  was  normal  without  any  sign 
of  hyper-  or  hypo-function.  These  adults  con- 
firm the  generally  admitted  fact  of  the  em- 
bryological,  anatomical  and  functional  inde- 
pendence of  the  parathyroids  and  the  thyroid; 

Hair. — Pfeiflfer  and  Mayer  noted  a  great 
shedding  of  hair  in  rats  during  tetan3^ 

Paraesthesia. — Vassale  noted,  in  a  bitch  after 
he  had  removed  the  three  parathyroids  during 
the  period  of  lactation,  a  pruritus  of  the  nose. 
Erdheim  pointed  out  that  after  tetany  in  rats, 
due  to  removal  of  the  parathyroids,  they  spent 
a  great  part  of  the  day  in  making  a  toilet  for 
their  nose.  They  even  used,  in  addition  to 
their  anterior  extremities,  their  posterior  ex- 
tremities to  scratch  their  nose,  and  did  it  con- 

1  Compt.  rend.  Sociele  de  Biologie,   1910,  p.  818. 


tinuously  and  in  a  cramp-like  manner  until 
they  were  tired.  Then  after  a  rest  they  con- 
tinued the  scratching.  Erdheim  has  also  noted 
in   tetany   of   pregnant   women   a   paraesthesia. 

Vincent  and  Jolly  and  Berkeley  have  alluded 
to  the  curious  "paw  shaking"  on  the  second 
day  after  removal  of  the  parathyroids.  We 
have  also  noted  this  action  in  the  cat,  as  though 
the  cat  had  wet  his  foot  by  stepping  in  water. 
It  is  a  paraesthesia,  and  probably  due  to  changes 
in  the  center  of  touch. 

Uterine  Inertia. — In  pregnant  women  who 
have  tetania  parathyreopriva,  abortion  has  en- 
sued; there  was  atony  of  the  uterus  and  tam- 
poning had  to  be  resorted  to.  I  have  shown 
that  the  parathyroid  extract  strongly  excites 
uterine  contraction,  and  its  absence  may  ac- 
count for  the  uterine  atony.  The  parathyroids 
have  close  relations  with  the  sexual  organs. 

Urinary  Secretion  in  Nephritis. — In  a  case  of 
chronic  interstitial  nephritis,  one  grain  of  the 
gland  three  times  a  day  by  the  mouth  increased 
the  quantity  of  urine  a  half  pint  daily  in  forty- 
eight  hours.  In  this  case,  a  man  of  65  years 
of  age,  it  seemed  to  produce  an  extremely  fre- 
quent desire  to  micturate. 

Glucose. — After  the  injection  of  nucleoproteid 
of  the  parathyroid  by  the  vein,  glucose  appeared 
in  the  urine  to  the  extent  of  1^/2  per  cent.,  as 
shown  by  the  fermentation  test  and  Fehling's 
test. 


36 


IT   MAY    BE    CONCLUDKD: 

(i)  That  the  parathyroids  are  embryologically, 
histologically  and  physiologically  distinct  from 
the  thyroids.  The  only  thing  they  have  in 
common  is  their  position  in  the  neck. 

(2)  The  parathyroids,  unlike  the  thyroids, 
contain  no  iodine. 

(3)  Deficiency  of  the  secretion  by  the  para- 
thyroids is  the  cause  of  tetany. 

(4)  The  tetany  from  removal  of  the  para- 
thyroids can  be  greatly  benefited  by  pituitary 
extract,  calcium,  strontium  and  parathyroid 
extract.  They  can  carry  the  patient  along  until 
the  small  piece  of  parathyroid  can  hypertrophy 
and  supply  the  secretion. 

(5)  The  grafting  of  a  parathyroid  is  a  cure  for 
tetany. 

(6)  When  the  parathyroids  cause  tetany, 
they  do  it  by  absence  of  their  secretion,  and  not 
by  calcium  changes. 

(7)  In  tetany  there  is  a  poison  in  the  blood 
which  has  been  found  to  kill  mice  when  the 
serum  is  injected. 

(8)  That  hypocalcification  is  affirmed  and 
denied  by  experimental  tests  to  exist  in  tetany. 
The  calcium  changes  are  only  an  epiphenome- 
non. 

(9)  Of  all  the  glandular  extracts  the  para- 
thyroids are  the  most  powerful  diuretics.  They 
act  directly  on  the  renal  epithelium,  as  the- 
urinary  secretion  is  increased  when  the  arterial 


37 

tension  is  lowered  from  the  beginning  of  the 
injection  of  nucleoproteid  by  the  jugular. 

(id)  The  parathyroids  increase  uterine  con- 
tractions and  intestinal  peristalsis. 

(ii)  When  locally  applied,  the  nucleoproteid 
of  the  parathyroid  dilated  the  pupil. 

(12)  The  nucleoproteid  of  the  parathyroid 
in  small  doses  momentarily  increases  and  then 
decreases  the  arterial  tension.  Large  doses 
decrease  it  at  once.  The  pulse  is  decreased 
by  powdered  parathyroid  and  then  increased. 

(13)  Nucleoproteid  increases  the  rate  of  res- 
piration.   Powdered  parathyroid  decreased  it. 

(14)  Large  doses  of  the  nucleoproteid  lowers 
the  temperature. 

I  cannot  close  with  better  words  than  those 
uttered  to  the  students  of  this  college  in  1896, 
in  an  introductory  lecture  by  me.  They  are 
as  true  now  as  they  were  thirteen  years  ago. 

Glandular  physiology,  in  its  wide-spread  rami- 
fications, applied  to  other  ductless  glands  of 
the  body,  has  revolutionized  many  parts  of 
physiology  and  pathology.  It  is  only  in  its 
infancy.  Its  maze  of  metabolic  changes  hold 
many  facts  to  be  discovered.  The  secretion 
of  the  ductless  gland  opens  up  new  avenues 
of  investigation,  which  wiU  enrich  the  science 
of  physiology  and  the  practical  application  of 
these  facts  in  therapeutics.  We  have  a  silent 
and  hitherto  unsuspected  secretion  going  on 
which  plays  a  most  important  and  unknown 
part  in  our  economy. 


38 

Very  potent- remedies  are  the  ductless  glands, 
where  but  a  few  millionths  of  a  grain  of  a  gland, 
like  the  adrenal,  greatly  elevated  arterial  tension. 
Several  of  these  animal  extracts,  as  I  have 
shown,  are  thermogenic  agents;  others  are 
not.  Some,  like  the  thyroid,  greatly  depress 
the  rate  of  the  heart. 

When  we  see  the  cures  produced  by  the 
thyroid  powder,  in  myxedema,  cretinism,  and 
obesity,  when  we  see  the  changes  of  acromegaly 
arrested  by  the  pituitary,  Addison's  disease 
improved  by  the  adrenals,  we  can  not  help 
noting  their  power.  We  see  in  the  action  of 
these  extracts  the  simple  external  manifesta- 
tions of  the  great  forces  at  play  in  the  nutrition 
of  the  economy. 

REFERENCES : 

Quest:   Wiener  Klinische  Wochenschrift,   1906. 

NETTER:  Comptes  Rendus  de  la  Societe  de  Biologic, 
1907,  page  376. 

HagEnbach:  Mitteilungen  aus  den  Greanzgebieten  der 
Medizin  iind  Chinirgie,  1907,  p.  330. 

Erdheim:  Mitteilungen  aus  den  Grenzgebieten  der 
Medizin  and  Chirurgie,  Band  16,  Heft  4  X  5,  p.  632. 

Pfeiffer  und  Mayer:  Mitteilungen  aus  den  Grenz- 
gebieten der  Medizin  und  Chirurgie,  1907,  p.  379. 

MacCallum:  The  Physiology  and  Pathology  of  the 
Parath3n-oid  Glands.  Proceedings  of  the  Pathological 
Society  of  Philadelphia,  1908,  April  and  May. 

BEEBE:  The  Inhibition  of  Tetany  by  Extract  of  the 
Parath5T-oid.     Am.  Journal  of  Physiology,  Vol.  XIX. 

W.  G.  MacCallum  and  Voegtlin:  Journal  of  Ex- 
pcri'ynental  Medicine,  Jan.,   1906. 

Berkeley  and  Beebe:  Journal  of  Medical  Research, 
Feb.,  1909. 


39 

Bell   and    Hick:  British    Medical   Journal,    1909,    p. 

517- 

PEPERE:  Le  Ghiandole  Paratiroidee,  1906. 

Vincent  and  Jolly:  Journal  of  Physiology,  Vol; 
XXXII,  p.  65. 

W.  S.  Carter:  Texas  State  Journal  of  Medicine,  Jan., 
1908. 

Moussu:  Recherches  sur  les  Fonctions  Thyroidienne 
et  Parathyroidienne,   1897. 

Minkiewitsch:  Tetania  parathyreopriva  und  Hyper- 
parathyreosis,   1908. 

Forsyth,  David:  The  Quarterly  Journal  of  Medicine, 
1908,  Vol.  I,  Nos.  2  and  3. 

Geiss:  Ueber  tetanie  tuich  partial  strumectomie-ln- 
augural   Dissertation  Gottingen,    1902. 

A.  BiEdl:  Innere  Secretion,   1904. 

A.  Frouin:  La  Presse  Medicate,  1909,  No.  62,   p.   609. 

L.  CoTONi:  Revue  de  Medicine,  1909,  No.  8,  p.  615. 

Karl  Petren:  Upsala  Lakareforenings  Forhandlingar, 
i909-'io,  Haft  102,  p.  I. 


SECOND  LECTURE— THE  PITUITARY/ 

Gentlemen: — Last  year  the  parathyroids  served 
as  a  subject  for  the  introductory  lecture.  As 
the  ductless  glands  have  been  the  object  of 
much  experimentation  in  conjunction  with  Dr. 
J.  C.  Scott  in  our  laboratory,  I  have  selected 
this  year  the  pituitary  gland,  which  is  fast 
coming  into  great  prominence  both  in  surgical 
and  in  therapeutical  relations.  In  the  lecture 
I  shall  use  the  words  hypophysis  and  pituitary 
as  interchangeable  in  meaning.  For  excess  of 
secretion,  hyperhypophysy ;  for  deficit  of  secre- 
tion, hypohypophysy.  I  prefer  these  words 
to  hyperpituitarism  and  hypopituitarism. 

I  shall  not  consider  the  surgical  procedures 
for  the  removal  of  the  gland.  In  this  lecture 
only  the  main  points  will  be  taken  up,  but  they 
will  bear  on  the  practical  side  of  medicine. 

The  hypophysis  is  situated  at  the  base  of  the 
brain  in  the  sella  turcica  of  the  sphenoid  bone  (Fig. 
6).     In  man  the  pituitary  weighs  about  }4  gram. 

Diameters  of  Pituitary  Fossa. — Porier  makes 
the  diameters  of  the  pituitary  fossa  as  follows  •? 

Male  (anterior-posterior.)  Female. 

0.75  to  1.45  centimeters  0.75  to  1.30  centimeters 

Transverse 

0.70  to  1.50  centimeters  0.80  to  1.50  centimeters 

Depth 
0.60  to  1.20  centimeters  0.60  to  1.39  centimeters 

1  Lecture    delivered    Sept.    28,     1910,    before    the    Sophomore 
class  of  the  Medico-Chirurgical  College  of  Philadelphia. 

2  Jaugeas,  Les  Rayons  de  Rontgen  dans  le  diagnostic  et  iraii- 
ment  des  Tumeurs  Hypophys aires.   1909.  __ 


41 

Chemical  Nature. — Simpson  and  Hunter  found 
in  eleven  fresh  pituitaries  of  the  slaughter-house 
from  the  sheep  a  minimal  amount  of  iodine — 


Fig.  6. — Mesial  section  through  the  pituitary  region  in  the  child. 

A.  Foramen  of  Monro. 

B.  Anterior  Commissure. 

C.  Ventricle  III. 

D.  Corpus  mammillare. 

E.  Subarachnoid  tissue  in  cisterna  basalis. 

F.  Infundibulum. 

G.  Pituitary  body. 
H.  Cisterna  pontis. 
I.  Basi-occipital. 

J.  Sphenoidal  sinus. 

not    more  than    0.005    milligram.      In     sheep 
they   removed   the   thyroid,  leaving  behind   the 


two  external  parathyroids,  and  after  forty- 
seven  to  fifty-six  days  the  sheep  were  killed, 
but  no  iodine  was  found  in  their  pituitaries.^ 
Halliburton,  Candler  and  Sikes^  found  no  iodine 
in  the  human  pituitary  by  Baumann's  method. 

Dr.  H.  Gideon  Wells^  analyzed  twenty-two 
pituitaries  from  patients  who  had  not  received 
iodine  while  in  the  hospital.  He  did  not  find 
a  trace  of  iodine  by  Baumann's  method.  In 
three  glands  from  patients  who  had  received 
iodine  he  found  a  trace  of  iodine,  probably  about 
0.02  milligram.  The  inference  is  that  the 
pituitary  contains  no  iodine. 

W.  Neubert  found  glycogen  constantly  in 
the  epithelium  of  the  colloid-  cysts  lying  in  the 
boundary  between  the  anterior  and  posterior 
lobes.  It  is  also  found  in  the  nervous  portion 
of  the  hypophysis.  This  glycogen  is  markedly 
increased  in  diabetic  cases.  ^ 

Histology  — The  pituitary  is  composed  of  three 
parts:  (i)  the  large  anterior  epithelial  lobe, 
pars  anterior;  (2)  a  much  smaller  posterior, 
nervous  or  infundibular  lobe, .  pars  posterior; 
and  (3)  the  pars  intermedia.  The  ectoderm 
of  the  mouth  (Rathke's  pouch)  originates  the 
anterior  lobe,  which  soon  becomes  a  glandular 
structure.     An    outgrowth    from    the    floor    of 

'  Quarterly  Journal  of  Experimental  Physiology,  Vol.  Ill,  No. 
2.  p.  121. 

-  Quarterly  Journal  of  Experimental  Physiology,  1909,  p. 
229. 

^  Journal  of  Biological  Chemistry.  Vol.  VII,  No.  4,  p.  250. 

"^  Beitrdge  zur  Path.  Anat.  und  zur  Allg.  Path..  1909,  XIV,  38; 
Journal  of  Am.  Medical  Association.  No.  24,  p.  2023,  1909. 


43 

the  third  ventricle  from  the  infundibular  pouch 
of  the  thalmencephalon,  the  mid-brain,  de- 
velops the  posterior  lobe.  The  posterior  lobe 
consists  of  two  parts :  ( i )  the  neuroglia  cells 
and  fibers  with  ependymal  cells,  and  (2)  the 
pars  intermedia,  composed  of  epithelial  cells 
from  a  diverticulum  of  buccal  epithelium,  the 
posterior  pharynx,  and  is  ectodermic  in  origin. 
Herring  finds  in  the  cat  the  posterior  lobe 
of  the  pituitary  is  hollow  and  its  cavity  is  in 
free  communication  with  the  third  ventricle 
of  the  brain,  while  the  epithelium  of  the  anterior 
lobe  affords  a  nearly  complete  investment  of 
the  posterior  lobe.  In  the  dog  the  posterior 
lobe  is  solid,  but  the  neck  is  hollow  and  in  com- 
munication with  the  third  ventricle.  The 
epithelial  part  of  the  pituitary  is  composed 
of  two  distinct  parts,  an  anterior  lobe  consist- 
ing of  solid  columns  of  cells,  and  a  pars  inter- 
media which  lies  between  the  anterior  lobe 
and  the  nervous  tissue,  forming  a  close-fitting 
investment  of  the  latter.  The  anterior  lobe 
contains  cells  which  are  clear  or  hold  in  their 
protoplasm  varying  amounts  of  granules  which 
stain  deeply.  The  pars  intermedia  consists 
of  finely  granular  cells,  in  layers  of  various 
thicknesses  and  closely  applied  to  the  posterior 
lobe.  Colloid  material  is  found  between  the 
cells  of  the  pars  intermedia,  which  appears 
to  pass  into  the  nervous  substance  of  the  gland 
and  then  into  the  third  ventricle.  The  infundib- 
ular   or    nervous    part  is  made  up  of  neuroglia 


44 

cells  and  fibers.  It  has  no  true  nerve  cells, 
and  the  nerves  supplying  the  pituitary  probably 
reach  it  through  the  sympathetic  fibers  supply- 
ing the  blood  vessels.  The  nervous  part  con- 
tains columns  of  epithelial  cells  from  the  pars 
intermedia,  and  islets  of  these  cells  are  found 
in  the  substance  of  the  infundibular  lobe.  The 
nervous  part  contains  large  amounts  of  colloid 
like  that  of  the  thyroid.^ 

The  anterior  lobe  is  a  gland  which  must  dis- 
charge its  secretion  directly  into  the  vascular 
sinuses.  The  secretion  of  the  pars  intermedia 
seems  to  be  secreted  into  the  substance  of  the 
brain. 

The  function  of  the  pars  intermedia  is  to 
generate  a  colloid  material  which  acts  upon 
the  circulation  and  the  kidneys. 

Haberfeld  has  examined  the  pharynx  in  man 
for  remains  of  the  embryonal  diverticulum 
which  finally  forms  the  pituitary.  He  in- 
vestigated fifty-one  subjects  whose  ages  ranged 
from  fetal  life  to  old  age.  In  all  cases  he  found 
a  definite  structure  which  he  calls  the  -phsLryn- 
geal  pituitary  gland.  It  is  made  up  of  a  string 
of  cells,  is  5  millimeters  in  length,  and  runs 
immediately  behind  the  vomer  upwards  and 
backwards.  It  is  composed  of  cells  similar  to 
those  in  the  pituitary,  but  the  chief  cells  are 
the  "Hauptzellen.  "- 

1  Herring,     Quarterly     Journal     of     Experimental     Physiology, 
1908.  Vol.  1,  No.  2,  p.  156. 

^  Beilrdge  zur    Path.    Anat.     u.    zur    Allgemein    Path.,     1909, 

p.    133. 


45 

The  pars  anterior  contains  three  kinds  of 
cells:  (i)  the  " Hauptzellen ; "  (2)  Eosinophiles ; 
(3)  Basophiles.  Erdheim  and  Stumme  call  the 
eosinophiles  or  acidophiles  and  basophiles  or 
amphophiles  or  cyanophiles  because  their  proto- 
plasm intensely  takes  up  stains,  the  chromo- 
philes,  while  the  "Hauptzellen"  they  call 
chromophobes,  because  their  protoplasm  is  very 
difficult  to  stain.  The  most  numerous  cells 
are  the  eosinophiles,  the  next  in  number  the 
basophiles.  The  "Hauptzellen"  are  less  in 
number  than  the  eosinophiles  and  the  baso- 
philes, and  usually  are  found  in  the  center  of 
the  alveolus. 

The  importance  of  these  cells  in  the  secretion 
of  the  hypophysis  has  been  the  subject  of  several 
theories.  Thom  holds  that  the  strongly  stain- 
ing chromophile  cells  produce  a  secretion  in 
the  form  of  fine  granules.  Their  cell  walls  are 
indistinct,  the  nucleus  moves  towards  the  periph- 
ery, the  granules  escape  and  mix  with  an 
incolorable  secretory  material  furnished  by 
the  chromophobes.  Scaffidis,  like  Thom,  makes 
two  kinds  of  secretory  cells,  so  that  the  gland- 
ular secretion  is  a  mixture  of  two  processes 
of  secretion.  In  the  secretion  of  the  two  types 
of  cells,  one  reacts  to  an  acid,  the  other  reacts 
to  an  alkali;  these  both  concur  to  form  the 
colloid  secretion  of  the  hypophysis.  Taunois 
holds  a  view  similar  to  that  of  Scaffidis.^ 

The  majority  of  authors  believe   the  colloid 

1  Launois,  These,  Paris,   1904. 


46 

is  the  normal  secretion  of  the  hypophysis. 
Cagnetto  in  a  case  of  acromegaly  found  the 
chromophile  cells  and  colloid  increased,  while 
in  a  case  of  tumor  of  the  hypophysis  without 
acromegaly  both  chromophile  cells  and  colloid 
were  diminished.  A  few  authors  believe  they 
have  seen  the  passage  of  the  colloid  into  the 
blood. 

Comte'  in  1898  noted  an  increase  in  the  size 
of  the  pituitary  in  pregnancy.  Hrdheim  and 
Stumme-  have  examined  twenty-five  normal 
pituitaries.     They    make    three    types    of    cells. 

During  pregnancy  the  hypophysis  increases 
in  weight  and  size  and  this  increase  is  in  the 
pars  anterior,  the  pars  posterior  remaining 
unaltered.  At  the  end  of  pregnancy  the  "Haupt- 
zellen"  are  increased  so  much  in  number  that 
the  eosinophiles,  unchanged  in  number,  take 
the  second  place.  A  few  weeks  after  delivery 
the  pregnancy  cells  decrease  and  at  the  end  of 
the  second  year  post-partum  the  eosinophiles 
are  again  predominant.  The  number  of  baso- 
philes  remains  the  same  in  pregnancy.  The 
"Hauptzellen"  are  the  cells  in  which  the  pe- 
culiar changes  caused  by  pregnancy  take  place, 
as  they  are  enormously  increased  and  con- 
siderably hypertrophied.  These  pregnancy  cells 
in  time  atrophy  and  become  the  "Hauptzellen." 
The   number   of    "pregnancy   cells"    by    multi- 

'  Comte.  Contribution  a  V Etude  de  I'hypophyse,  1898. 
*  Beiirdge  zur  Path.  Anat.  und   zur    Allgevieinun    Path.,    p.   1, 
1909. 


47 

para  is  undoubtedly  much  greater  than  in  the 
primipara. 

They  claim  that  a  skilled  histologist  can  diag- 
nose a  former  pregnancy  from  the  pituitary 
gland.  The  swelling  of  the  gland  is  quite  defi- 
nite and  in  two  cases  there  was  a  hernia  of 
the  gland  through  a  hole  in  the  dura  which 
accommodates  the  infundibulum. 

The  bloated  face,  the  swollen  lips  and  the 
enlargement  of  the  hands  have  been  referred 
by  Tandler  and  Gross  to  the  enlargement  of 
the  hypophysis  by  pregnancy — a  hypersecretion. 

These  facts  have  been  used  as  an  argument 
to  support  the  theory  of  hypersecretion  in  acro- 
megaly., .  Von  Reuss  observed  a  bitemporal 
hemianopsia  in  the  course  of  a  14",  15"  and 
16"  pregnancy,  which  gradually  disappeared 
after  delivery.  He  thought  there  was  a  large 
pituitary  pressing  upon  the  optic  chiasm  which 
caused  the  hemianopsia. 

Coagulation  of  Blood. — Weil  and  Boye  and 
Levan  have  shown  in  rabbits,  dogs  and  man 
that  intravenously  the  posterior  lobe  causes 
coagulation  with  great  rapidity,  notwithstand- 
ing the  alkaline  solution  in  the  manometer 
tube.  After  an  injection  by  the  A'ein  of  the 
anterior  part  of  the  pituitary,  coagulation  is 
the  exception.  If  the  whole  pituitary  is  in- 
jected then  coagulation^  is  also  exceptional. 

Herry^  found  that  the  extract  of  fresh  organs 

1  Compt.  rendus  de  la  Soc.  de  Biologie,  p.  618,  1909. 

2  Compt.  rendus  de  la  Soc.  de  Biologie,  p.  603,  1910. 


48 

(as  spleen,  kidney,  lung,  liver,  thymus  and 
hypophysis)  more  completely  corrected  the  diffi- 
culty of  coagulation  of  the  blood  in  hemophilia 
than  fresh  serum.  Extracts  from  the  dried 
organs  did  not  coagulate  blood  as  well  as  the 
fresh  organs. 

Action  of  Pituitary  on  the  Circulation. — 
Oliver  and  Shaefer  (1895)  stated  that  aqueous 
or  saline  extracts  may  be  boiled  without  losing 
their  activity  and  when  injected  produced  a 
rise  of  blood  pressure.  They  also  showed  that 
it  was  due  to  an  action  on  the  arterioles.  Howell 
(1898)  found  that  it  was  the  infundibular  lobe 
which  elevated  blood  pressure.  He  also  noted 
a  slowing  of  the  heart.  Shaefer  and  Swale 
Vincent  (1899)  found  the  cardiac  slowing  ob- 
served was  not  constant  and  that  slowing  en- 
sues after  section  of  vagi  or  previous  atropiniza- 
tion.  Hence,  the  seat  of  the  slowing  is  periph- 
eral. Adrenalin  acts  on  the  vagus  center. 
Shaefer  found  that  the  second  or  third  dose 
did  not  produce  a  rise  but  invariably  a  fall 
which  lasts  but  a  short  time. 

Shaefer  and  Swale  Vincent  believe  this  to 
be  due  to  a  depressor  substance,  and  that  this 
substance  is  soluble  in  alcohol,  in  which  the 
pressor  substance  is  insoluble.  This  depressor 
substance  is  not  identical  with  choline  as  the 
previous  use  of  atropin  does  not  prevent  the 
fall  as  is  the  case  with  choline. 

Circulation,  Effect  of  Anterior  Lobe. — Dr.  W. 
J.    Hamburger    found,    as    previous    observers 


49 

did,  that  the  intravenous  injection  of  a  saline 
extract  of  the  anterior  lobe  caused  a  distinct 
fall  of  blood-pressure.  This  was  usually  ac- 
companied by  an  acceleration  and  weakening 
of  the  heart.  That  a  second  injection  im- 
mediately following  the  first  does  not  produce 
any  change  in  blood  pressure.  After  a  consid- 
erable interval  the  second  injection  produces 
a  fall.  In  a  number  of  dogs  the  fall  of  arterial 
tension  was  succeeded  by  an  apparent  toxic 
action  resulting  in  death.  The  depressor  sub- 
stance is  soluble  in  alcohol,  glycerin  and  salt 
solutions,  but  insoluble  in  ether. 

A  secondary  rise  above  normal  follows  the 
depressor  effect  produced  by  an  alcoholic  ex- 
tract of  the  anterior  lobe.^ 

Fodera  and  Pittau^  studied  the  hypophysis. 
They  did  not  confirm  Von  Cyon's  statement 
that  the  greatest  activity  was  in  boiled  ex- 
tracts, being  superior  to  those  obtained  in  the 
cold  or  at  a  temperature  below  that  of  ebulli- 
tion, or  that  the  extracts  of  dried  glands  were 
better  than  those  obtained  from  fresh  glands. 
They  could  not  find  the  slightest  difference 
in  their  activity.  They  experimented  upon 
frogs  and  rabbits.  Between  the  extracts  of 
the  posterior  lobe  as  a  whole  and  those  of  the 
posterior  lobe  deprived  of  the  small  epithelial 
layer   there   was   no    qualitative   difference   but 

1  American  Journal  of  Physiology,  Vol.  XXVI,  p.  178. 
^  Archives  Italienne    de    Biologie,     Tome     LII,    Fasc.     III.   p. 
370,  1909. 


50 

onlv    a   slight    quantitative    diflference    in    favor 
of  the  true  posterior  lobe. 

In  regard  to  the  question  of  Salvioli  and  Car- 
raro,  about  the  importance  of  the  epithelial 
layer  in  the  production  of  the  phenornena  of 
posterior  lobe,  they  answer  in  the  affirrnative. 
They  believe  that  the  epithelial  layer  secretes 
a  substance  which  penetrates  into  the  infundib- 
ular lobe  and  may  be  still  further  elaborated. 
The  anterior  lobe  is  completely  inactive,  as  the 
activity  of  the  whole  lobe  is  no  more  active 
than  the  posterior  lobe  alone.  They  obtained 
no  effect  upon  the  heart  and  blood  vessels  of 
'the  frog  by  pituitary  extracts.  In  dogs  they 
confirm  Salvioli  and  Carraro  that  the  extracts 
of  the  hypophysis  cause  a  short  characteristic 
diarrhea  followed  by  tenesmus.  Intravenous 
injections  are  active.  Hypodermic  injections 
and  use  by  the  mouth,  even  intracerebral 
injections  are  inefficacious.  Extracts  of  the 
hypophysis  of  the  cow,  when  given  in  large  doses 
to  dogs  and  repeated  many  times  a  day,  cause 
emaciation.  They  did  not  find  any  prophylactic 
or  anaphylactic  properties  by  intravenous  in- 
jections in  dogs. 

The  Active  Principle. — Is  there  more  than 
one  active  principle  in  pituitary;*  Malcolm 
obtained  different  results  in  metabolisni  be- 
tween the  fresh  and  dried  gland.  Shaefer  has 
obtained  diuretic  results  without  blood  pressure 
action.  Dale  has  thrown  considerable  doubt 
upon  the  theory  of  more  than  one  active  prin- 


51 

ciple.  We  have  found  pituitary  extracts  that 
did  not  elevate  blood-pressure  but  did  have 
diuretic  effects. 

Does  the  hypophysis  contain  adrenalin?  Both 
raise  blood  pressure,  both  dilate  the  pupil  of 
the  enucleated  frog's  eye,  both  subcutaneously 
produce  glycosuria  in  rabbits.  Adrenalin  fre- 
quently injected  produces  sclerosis  of  the  aorta. 
Meyers^  has  shown  that  pituitary  extract  can 
also  injure  the  blood  vessel.  W.  W.  Harvey 
has  produced  sclerotic  effects  in  the  coronary 
arteries  by  repeated  injections  of  the  hypophy- 
sis.- 

Borchardt^  noted  the  absence  of  adrenalin 
in  the  hypophysis,  since  Vulpian's  test,  the 
addition  of  iron  chloride,  produced  no  green 
color,  as  adrenalin  does.  There  are  two  reac- 
tions for  adrenalin,  which  are  very  sensitive 
and  characteristic.  The  first  is  that  of  Comes- 
sati.  It  is  a  red  color  by  the  oxidation  of 
adrenalin.  Comessati  used  a  2%  sublimate 
solution  as  an  oxygen  bearer;  but  Frankel 
and  Allers*  have  shown  that  the  reaction  ensues 
with  other  oxidizing  substances,  as  copper 
sulphate,  potassium  chlorate,  and  platinum 
chloride.  Frankel  and  Allers,^  have  proposed 
a  new  test  for  adrenalin.  Adrenalin  gives, 
with  a  slight  blue  shade,  a  red  color  in  the  pres- 
ence  of   some   phosphoric   acid,    heated   with   a 

1  Zeitschrijt  iiir  physiological  Chem.,    1903. 

-  Bio-Chemical  Journal,  p.  431,  Vol.  IV,  No.  9. 

3  Zeitschrift  fiir  Klin.  Med.,  Bd.  66. 

^  Miinchener  Med.  Woch-enschrift,  p.  1478.  1909. 


52 

A''/iooo  biniodate  of  sodium  solution.  A  dilu- 
tion 1 :  300,000  shows  a  perceptible  reaction. 
This  test  and  that  of  Comessati  with  pituitrin 
of  Parke,  Davis  &  Co.  showed  a  negative  reac- 
tion. 

Hence  '  adrenalin  and  the  active  principle 
of  the  pituitary  are  not  the  same  substance. 

Action  on  Kidneys. — Schafer  and  Herring^ 
have  shown  that  the  infundibular  part  of  the 
pituitary  body  yields  a  substance  soluble  in 
water  and  not  destroyed  by  boiling,  which  has 
a  specific  action  on  the  kidney,  dilating  the 
renal  vessels  and  increasing  the  secretion  from 
the  tubules.  If  the  urinary  flow  is  suppressed 
from  operative  procedures  or  the  anesthetic, 
it  causes  a  flow.  They  think  it  is  as  actively 
diuretic  as  caffeine  citrate.  They  found  when 
there  was  a  general  fall  of  blood  pressure  with 
no  increase,  but  even  a  shrinkage  of  the  vol- 
ume of  the  kidney,  a  diuretic  action,  indicating 
a  stimulation  of  the  renal  epithelium.  This 
shrinkage  of  the  kidney  precedes  the  dilata- 
tion in  some  cases.  Pituitary  was  found  to 
diminish  the  flow  of  pancreatic  juice. 

Hypodermically,  the  pituitary  also  slightly 
raises  blood  pressure,  dilates  the  kidney  ves- 
sels and  increases  the  rate  of  flow  of  urine. 
They  also  point  out  that  the  adrenals  and  pitui- 
tary each  consist  of  two  parts,  one  epithelium, 
the  other  part  of  neuroectodermic  origin.     The 

'  Philosophical   Transactions   of  the  Royal  Society   of   London, 
pp.  1-29. 


53 

epithelial  parts  of  these  two  glands  do  not  yield 
any  physiological  effect,  while  those  of  neuroecto- 
dermic  origin  furnish  substances  affecting  the 
heart  and  arteries.  Here  the  similarity  ends, 
for  adrenalin  excites  the  sympathetic  terminals 
in  general,  while  the  pituitary  does  not. 

Houghton  and  MerriP  have  studied  the  action 
of  adrenalin  and  the  active  principle  of  the 
pituitary  gland  upon  the  urinary  secretion. 
Pituitary  slowed  the  pulse  rate  after  the  use 
of  atropin  and  after  section  of  vagi.  Aldrich 
obtained  a  crystalline  picrate  and  a  sulphate 
from  the  infundibular  part  of  the  pituitary. 
They  found  adrenalin  to  increase  the  blood 
pressure  and  the  flow  of  urine.  They  experi- 
mented on  normal  man  for  several  days  where 
the  food,  drink,  habits,  exercise  and  work  were 
the  same.  Then  pituitary  extract  was  given 
internally.  They  found  only  a  slight  increase 
of  the  urine  in  man. 

Then  they  made  experiments  upon  dogs, 
anesthetized  by  morphine  and  chloretone  with 
cannulae  in  the  ureters.  The  drops  of  urine, 
were  recorded  with  the  blood  pressure  and  the 
respiratory  movements.  Adrenalin  increased  the 
blood  pressure  from  56  to  88  mim.  of  mercury 
which  within  six  minutes  had  returned  to  normal. 
The  urine  increased  from  8  minims  per  minute 
to  30  per  minute,  the  maximum  following 
closely  the  maximum  blood  pressure.  The  in- 
crease of  urinary  flow  continued  after  the  fall 

^Journal  Am.  Medical  Association,  1908,  p.   1849. 


54 

of  blood  pressure  to  normal,  and  at  the  end 
of  fifteen  minutes  it  was  the  same  as  at  the  be- 
ginning of  the  experiment.  They  also  per- 
fused excised  kidneys,  noting  the  flow  from 
the  renal  vein  and  ureter,  and  found  that  pitui- 
tary extract  added  to  saline  solution  made  the 
venous  flow  and  ureteral  flow  less  than  when 
saline  alone  was  used.  They  do  not  believe 
in  a  specific  action  on  the  kidney  cell,  and  if 
so  it  is  less  marked  than  in  the  case  of  a  i  per 
cent,  saline  solution.  It  is  due  to  a  rise  in  blood 
pressure. 

Pal  noted  in  cats  that  the  diuretic  effect  of 
pituitary  extract  was  marked,  when  given  in- 
travenously. He  emptied  the  bladder  of  a 
cat  to  which  morphia  and  curare  had  been  given, 
and  found  that  the  intravenous  injection  of 
two  cubic  centimeters  of  pituitary  extract 
filled  the  bladder  in  a  very  short  time.  As  is 
well  known,  the  bladder  is  generally  empty 
after  curare  narcosis.  Pal's  experiments  as  to 
the  size  of  the  kidney  after  the  use  of  pituitary 
were  not  uniform  like  those  of  Schafer.  Pal 
found  that  pituitary  dilated  the  renal  artery 
and  contracted  the  coronary  arteries. 

Pal,'  hke  Langendorff,  found  adrenalin  di- 
lated the  coronary  artery,  while  contracting 
the  renal  and  other  arteries.  He  found  pituitary 
extract  to  dilate  the  renal  arteries,  but  to  con- 
tract the  coronary  and  other  arteries. 

We   made   20   experiments.     The    volume    of 

Wiener  Medizinische  Wochenschrijt.  1909,  p.  138. 


55 

the  kidney  was  registered  by  means  of  an  air 
oncometer  and  Albrecht's  piston  recorder. 

Our  experiments  were  mainly  made  upon 
cats;  a  few  were  made  with  rabbits.  The  ani- 
mal was  bound  down,  given  5  cc.  of  paralde- 
hyde by  the  mouth.  Then  chloroform  was 
given.  The  abdomen  was  opened  in  the  median 
line  over  the  bladder,  the  bladder  drawn  out 
and  an  incision  made  into  it.  A  funnel-shaped 
glass  tube  with  a  flange  was  inserted  into  the 
bladder  and  the  bladder  tied  tightly  about  the 
flange.  Then  the  bladder  was  filled  with  the 
urine  previously  obtained  from  the  bladder. 
If  this  was  not  sufficient  to  fill  the  bladder, 
Ringer's  solution  was  added.  By  means  of 
a  piece  of  rubber  tubing  attached  to  the  funnel- 
shaped  glass  tube  the  urine  was  allowed  to 
drop  into  the  capsule.  This  was  permitted 
for  about  fifteen  or  twenty  minutes  when  each 
drop  was  noted  on  the  smoked  drum  with  an 
electric  marker.  Then  the  extract  of  the  gland, 
rubbed  up  with  distilled  water  and  filtered, 
was  injected  into  the  jugular  and  the  drops  of 
urine  again  noted  on  the  drum.  The  bladder 
was  kept  moist  with  absorbent  cotton  wet 
with  Ringer's  solution.  The  blood  pressure 
was  frequently  noted  at  the  time  the  drops  of 
urine  were  registered. 

The  infundibular  part  of  the  pituitary  is  a 
diuretic.  As  it  does  not  markedly  increase 
the  general  arterial  tension  except  for  a  moment 
and  then  lowers  it,  it  is  inferable  that  the  very 


56 

short  rise  of  blood  pressure  does  not  produce 
diuresis  which  continues  a  considerable  time 
after  the  rise  of  blood  pressure. 

As  the  variations  of  arterial  tension  do  not 
play  any  part  in  the  diuresis,  it  must  be  referred 
to  an  action  of  the  renal  epithelium  itself  (Fig.  7). 

Schaefer  states  that  the  anterior  part  of  the 
pituitary  has  no  diuretic  effect.  The  pars 
intermedia  also  increases  the  secretion  of  urine. 

Glycosuria. — It  is  one  of  the  most  frequent 
symptoms  of  acromegaly.  Hansemann  found 
it  19  times  in  97  cases,  while  Marie  observed 
it  in  one- third  to  one-half  of  his  cases.  In  all 
these  cases  of  acromegaly  with  glycosuria  they 
found  hypertrophy,  glioma,  sarcoma,  adenoma 
and  epithelioma  of  the  pituitar}.  Thaon  in 
a  case  of  beginning  neoplasm  of  the  hypophysis 
found  a  notable  hypertrophy  of  the  islets  of 
Langerhans,  but  there  was  no  diabetes.  Lorand 
considered  that  lesions  of  the  thyroid  and  pan- 
creas played  a  great  part  in  the  production  of 
glycosuria  in  acromegalic  patients. 

Caselli  destroyed  the  posterior  lobe  in  a  dog 
without  touching  the  anterior  lobe,  and  gly- 
cosuria appeared.^ 

Polyuria  and  sometimes  glycosuria  occurs 
in  animals  with  a  partial  removal  of  the  anterior 
and  a  total  removal  of  the  posterior  lobe  accord- 
ing to  Gushing. 

Borchardt-   has  proved   that   the   hypodermic 

'  Presbeunu,  These.  1909.  p.  70. 

-  Zeilschrift  fiir  Klinische  Medizin.    1908,    Band   66,   p.   332. 


.i(v;V/^^''^'^^ 


/VlVWVW\ 


'm^'^'^''"^' 


1-~~t-1 


:ond   line  from  top) 


57 

use  of  the  pituitary  produced  a  small  amount 
of  sugar  in  the  urine.  He  used  the  boiled 
filtered  infusion  of  the  gland,  which  was  in- 
jected hypodermically  in  rabbits  and  dogs. 
The  quantity  of  sugar  obtained  by  him  varied 
from  a  trace  to  4.2  per  cent.  The  absolute 
quantity  of  sugar  was  very  small,  not  more 
than  a  centigram.  The  sugar  usually  began 
to  appear  in  the  urine  three  hours  after  the 
injection.  The  amount  of  sugar  excreted  was 
extraordinarily  variable  and  to  a  great  degree 
independent  of  the  amount  of  the  gland  in- 
jected. He  found  that  pituitary  produced 
glycosuria  more  easily  in  rabbits  than  in  dogs. 

Infundibulin. — -We  have  also  studied  the  efi'ect 
of  injections  of  infundibulin  in  rabbits  and  cats. 
The  number  of  our  experiments  was  fifteen.  The 
tests  for  glucose  were  Fehling's,  fermentation  and 
the  phenylhydrazine  tests.  The  injection  of 
these  extracts  of  the  glands  proceeds  on  the 
theory  that  they  act  like  a  hypersecretion  of 
the  gland.  The  first  extract  used  was  infundib- 
ulin 20  per  cent,  extract  of  the  pituitary  (Bur- 
roughs Wellcome,  &  Co.).  Borchardt  used  the 
whole  gland  to  produce  sugar.  Falta  was 
unable  to  obtain  in  rabbits  any  glycosuria  with 
pituitrin,  which  is  obtained  from  the  infundib- 
ular part  of  the  pituitary. 

We  have  made  several  experiments  with 
infundibulin,  of  which  we  injected  i  cc.  into 
the  muscles  of  the  rabbit,  as  Meltzer  has  shown 
that   adrenalin   is   more   rapidly   absorbed    here 


58 

than  under  the  skin.  In  all  cases  at  the  end 
of  two  and  a  half  hours  we  found  glucose  in 
the  urine,  the  amount  being  about  one-eighth 
per  cent. 

In  cats  intramuscular  and  intraperitoneal 
injection  of  the  infundibulin  produced  similar 
results.  In  acromegaly  Hinsdale  found  in  an 
analysis  of  130  cases  that  10.8  per  cent,  had 
sugar.  Borchardt  from  an  analysis  of  176 
cases  of  acromegaly  holds  that  glycosuria  is 
more  regularly  associated  with  this  disease 
than  with  any  other.  However,  there  are 
cases  of  tumor  of  the  hypophysis  without 
acromegaly  and  which  are  not  complicated  with 
diabetes.  KoUaritz  has  collected  51  cases  of 
this  nature.  From  our  experiments  we  must 
infer  that  the  glycosuria  is  due  to  a  hyper- 
secretion of  the  infundibular  part  of  the  hypophy- 
sis, perhaps  of  the  pars  intermedia. 

Seat  of  the  Glycosuria:  (i)  Removal  of  Thy- 
roid.—In  etherized  cats  we  extirpated  the 
thyroid,  leaving  two  or  more  parathyroids. 
On  the  following  day  we  found  sugar  in  the  urine 
in  a  few  cases.  A  similar  result  after  removal 
of  the  thyroid  has  been  found  in  dogs  by  Fal- 
kenberg  and  Rahel  Hirsch.^  Falta,  however, 
did  not  obtain  it  in  dogs.  We  found,  however, 
that  the  injections  per  jugular  of  the  same  dose  of 
infundibulin  in  the  cat  after  the  absence  of 
the  thyroid  was  followed  by  a  decrease  in  the 
amount  of  sugar  as  compared  with  those  animals 

'  Zeitschrift  fiir  Klinische  Medicin,  1908.  p.  6. 


59 

whose  thyroid  was  intact.  Before  the  removal 
of  the  thyroid,  infundibuHn  caused  3  to  4  per 
cent,  of  sugar  in  the  urine;  after  the  removal, 
I  to  2  per  cent.  We  took  care  that  the  binding 
down  and  the  etherization  did  not  produce 
glycosuria. 

(2)  Removal  of  Adrenals. — In  the  etherized 
cat  we  removed  the  adrenals  with  the  most 
careful  antiseptic  precautions.  As  they  usually 
die  on  the  following  day,  we  injected  immediately 
on  the  same  day  the  infundibulin.  It  was 
given  by  the  jugular.  In  all  cases  sugar  ap- 
peared in  the  urine.  However,  Nishi  has  shown 
that  removal  of  adrenals  is  followed  by  hyper- 
glycemia. 

(3)  Splanchnicotomy. — In  cutting  both  splanch- 
nics  in  the  cat  we  followed  the  procedure 
of  Schultze.^  The  animals  were  etherized 
and  the  strictest  antiseptic  precautions  fol- 
lowed. The  abdomen  was  closed  by  suture 
and  the  animals  placed  in  the  cage  until  the 
next  day.  Then  they  were  again  etherized, 
jugular  prepared  and  infundibulin  injected. 
But  at  no  time  afterward  did  we  observe  any 
sugar  in  the  urine.  Pollak^  in  a  classification 
of  the  glycosurias  found  that  adrenalin  pro- 
duces sugar  in  the  urine  after  splanchnicotomy, 
being  an  agent  which  stimulates  the  terminals 
of  a  sympathetic  nerve.  The  glycosuria  of 
cafifein   does   not   ensue   after   splanchnicotomy. 

1  Archiv.    fiir    Experimentelle    Pathologie    und    Pharmakologie, 
Band  43,  p.    189. 

2  Archiv.  f.  ex.  Path.  u.  Pharmakol,  1909,  Band  61,  p.  376. 


6o 

According  to  Macleod,  curare  does  not  cause 
any  sugar  in  the  urine  after  section  of  the  splanch- 
nics. 

As  section  of  the  splanchnics  arrests  glycosuria 
we  must  consider  it  due  to  an  action  of  infundib- 
ulin  on  the  diabetic  center  in  the  medulla 
acting  through  the  splanchnics  on  the  glycogen 
of  the  liver.  If  the  sympathetics  influence 
the  adrenals,  who  then  actuate  the  glycogen 
in  the  liver,  is  a  c^uestion  not  decided  by  these 
experiments. 

Stimulant  of  Ufistriped  Fibers. — Dale^  used  a 
5  per  cent,  acid  decoction  of  the  fresh  posterior 
lobes  of  ox  pituitaries.  He  found  vaso-con- 
striction  of  the  pulmonary  arteries  on  per- 
fusion of  lungs,  which  does  not  happen  with 
adrenahn.  It  also  constricted  the  coronary 
arteries;  adrenalin  dilates  them.  In  perfused 
mammalian  heart  (rabbit)  the  ventricle  beat 
becomes  slightly  slower  and  considerably  more 
vigorous;  later,  with  persistent  retardation, 
it  becomes  weaker  than  before  the  injection. 
All  these  changes  ensue  after  an  atropinization, 
which  excludes  any  action  on  the  vagus.  Hence 
the  action  on  the  heart  beat  is  probably  due 
to  a  direct  effect  on  the  heart  muscle.  It  con- 
stricts the  muscular  capsule  of  the  spleen.  It 
also  produced  powerful  uterine  contractions. 
On  the  intestines,  in  dogs,  he  has  seen  the  move- 
ments inhibited  even  when  the  splanchnics 
were  cut.     Isolated  pieces  of  intestine  contract, 

'  Biocliemical  Jmirnal,  Vol.  IV,  No.  9,  p.  427,  1909. 


6i 

though  but  feebly,  when  pituitary  extract  is 
added.  It  is  probable  the  inhibition  just  men- 
tioned is  due  to  intense  anemia  of  the  intestine 
which  the  drug  produces  by  vaso-constriction. 
Hence  the  plain  muscle  of  bladder  and  intes- 
tine contract  in  response  to  pituitary  extract, 
but  their  sensitiveness  is  small  in  comparison 
to  that  of  some  organs.  Ergotoxine  annuls 
the  motor  "effects  of  the  sympathetic  nerves 
and  the  action  of  adrenalin,  so  that  the  latter 
produces  in'  the  cat  a  fall  of  blood  pressure 
and  relaxation  of  the  pregnant  uterus  instead 
of  the  customary  rise  and  uterine  contraction. 
But  pituitary  extract  acts  after  ergotoxine  on 
the  arteries,  contracting  them  and  the  uterine 
muscle. 

He  infers  that  the  characteristic  action  of 
the  infundibular  part  of  the  pituitary  is  to  stimu- 
late plain  muscle  fiber.  There  are  no  two  active 
principles,  the  pressor  and  diuretic  according 
to  Dale. 

Action  on  Intestinal  Peristalsis. — Bell  has 
shown  that  infundibular  extracts  have  an  ac- 
tion upon  intestinal  peristalsis  in  pithed  rab- 
bits, and  he  has  advised  its  use  in  intestinal 
paresis  after  abdominal  operation.  Our  ex- 
periments were  made  upon  etherized  rabbits. 
A  brass  cannula  with  a  rubber  balloon  over 
its  end  was  inserted  into  the  small  intestine, 
near  the  stomach  end.  It  was  attached  to 
Albrecht's  piston  recorder  and  the  normal 
movements    were    registered.      Then  the  infun- 


62 


dibulin  was  injected  per  jugular  and  the  subse- 
quent movements  of  the  intestine  noted.  It 
had  a  marked  action  as  is  shown  in  Fig.  8. 

Action  upon  the  Uterus. — H.  H.  Dale,  Bell 
and  Hick  have  shown  that  infundibulin  is  a 
uterine  stimulant.  Our  experiments  were  made 
upon  etherized  cats  and  rabbits.  The  abdominal 
cavity  opened,  the  head  in  the  Malassez  holder 
elevated  and  the  opened  walls  of  the  abdomen 
attached  by  hooks  to  a  transverse  bar.  The 
pelvic  cavity  was  filled  with  normal  saline, 
heated  to  about  the  temperature  of  the  body  and 
kept  so  by  frequent  additions.  This  solution 
kept  the  uterus  bathed.  Then,  as  Cushny 
has  advised,  we  attached  two  threads  to  the 
uterus  and  the  other  ends  of  the  thread  to  a 
myocardiographic  lever  which  registered  the 
contractions  of  the  uterus.  It  was  a  strong 
stimulant  of  uterine  contraction,  as  Fig.  9 
shows. 

Prof.  Von  Frankl-Hochwart  and  Frohlich 
in  the  rabbit  found  that  pituitrin  by  the  vein 
made  the  hypogastric  nerve  much  more  irritable, 
and  also  the  uterus  itself  much  more  active, 
when  the  faradic  current  was  applied  to  the  hypo- 
gastric nerve.  This  uterine  action  is  independ- 
ent of  blood  pressure.  Only  the  first  injection 
is  active  as  is  the  case  in  the  action  of  pituitrin 
upon  heart  and  blood  vessels. 

Bladder. — Von.  Frankl-Hochwart  and  Frohlich' 
used  pituitrin.     In  cats   and   dogs  pituitrin   ex- 

1  Wiener  Ktinische  Wochensciirifl.   1909.  p.  982. 


63 

cited  the  muscle  of  the  bladder  to  a  great  de- 
gree and  also  considerably  increased  the  ex- 
citability of  the  motor  nerves  of  the  nervus 
pelvicus  as  measured  by  the  distance  between 

:  coils  of  a  DuBois  inductorium.  They  used 
It  intravenously.  Before  the  injection,  the  blad- 
der contracted  when  the  nervus  pelvicus  was 
irritated  with  the  secondary  coil  at  19  cm. 
But  after  the  injection  of  0.5  pituitrin  the  blad- 
der contracted  at  26.  The  action  was  marked 
and  constant.  We  have  repeated  this  ex- 
periment in  cats.  The  nervus  pelvicus  was 
placed  on  Ludwig's  shielded  electrodes,  and 
a  hollow  glass  tube  with  a  short  arm  bent  at 
right  angles  was  bound  in  the  neck  of  the  blad- 
der. Then  we  used  the  weakest  faradic  cur- 
rent that  would  make  the  warm  Ringer  solu- 
tion mount  up  the  tube.  It  was  20  cm.  After 
injecting  one  cc.  of  20  per  cent,  extract  of  in- 
fundibular part  of  the  gland  irritation  of  the 
nerve  causes  an  ascent  of  the  fluid  when  the 
DuBois  coils  were  separated  28  cm.  We  also 
attached  the  bladder  to  a  water  manometer, 
opening  the  abdomen  and  severing  the  ureters, 
then  closing  the  abdomen  except  where  the  tube 
attached  to  the  manometer  was  connected. 
In  this  way  we  had  a  registration  of  the  move- 
ments of  the  bladder. 

When  the  infundibulin  was  injected  we  ob- 
tained a  marked  vesical  contraction  (Fig.  10.) 
If,  however,  the  nervi  pelvici  were  cut  then 
infundibulin    had  •  hardly    any    effect,    a    slight 


64 

increase  at  times  of  the  contraction  of  the  blad- 
der. These  experiments  prove  that  infundib- 
ulin  mainly  excites  the  bladder  by  an  action 
on  the  central  nervous  system. 

In  acromegaly  there  are  bladder  troubles, 
perhaps  due  to  hyperhypophysy,  or  pressure 
on  a  vesical  reflex  center  of  2"  order  in  locus 
niger. 

Actioyi  on  the  Pupil. — W.  Cramer^  noted  that 
extracts  of  the  posterior  lobe  of  the  pituitary 
body  of  the  ox  produced  a  distinct  dilatation 
of  the  pupil  of  the  enucleated  eye  of  the  frog. 
The  principle  is  distinct  from  that  body  in  the 
pituitary  which  produces  diuresis.  Ott  and 
Scott-  found  that  the  pituitary  in  the  rabbit 
dilates  the  pupil  after  removal  twenty-four 
hours  previously  of  the  superior  cervical  ganglion. 
It  was  used  locally,  by  the  jugular,  and  sub- 
cutaneously.  In  the  normal  eye  no  effect  en- 
sued. Pituitrin  has  the  same  effect,  showng 
it  is  the  infundibular  part  that  dilates  the  pupil. 

Von  Frankl-Hochwart  and  Frohlich  found 
by  intravenous  injection  of  pituitrin  a  narrow- 
ing of  the  pupil. ^ 

Temperature. — Mairet  and  Bosc  have  shown 
that  pituitary  extracts  when  injected  elevate 
the  temperature.  Narbut  found  after  removal 
of  the  hypophysis  a  lowering  of  the  tempera- 
ture on  the  day  of  the  operation  and  a  marked 

1  Quarterly    Journal    of    Experimental    Physiology,    Vol.    I,    p. 
187,  April,  1908. 

2  Tlie  New  York  Medical  Journai.  Dec,  1908. 

8  Wietier  Klinische  Wochenschrift,  p.  982.  1908,  July  8. 


65 

sinking  of  it  before  death.  Vassale  and  Sacchi 
also  noted  a  lowering  of  temperature  after 
removal  of  pituitary.  Injections  of  the 
hypophysis  in  these  cases  elevated  the  tempera- 
ture. 

Cushing  found  in  animals  suffering  from  hypo- 
pituitarism a  rise  of  2°  to  4°  C.  by  the  injection 
of  the  boiled  pars  anterior. 

After  a  partial  removal  of  the  pars  anterior 
and  an  entire  removal  of  the  posterior  lobe 
the  temperature  of  the  body  just  before  the 
death  fell  to  63.5°  (Cushing).  We  have  seen  the 
temperature  fall  to  94°,  in  monkeys  after  destruc- 
tion of  the  pars  anterior  by  the  operation  of 
Paulesco. 

Removal  of  Pituitary. — In  1886,  Horsely  first 
made  experiments  for  the  removal  of  the 
hypophysis  on  two  dogs.  They  soon  died  without 
any  special  disturbance.  During  the  hfe  of  the 
animals  he  noted  an  increase  of  the  excitability 
of  the  motor  centers.  A  weak  electric  irrita- 
tion of  them  caused  unusually  strong  clonic  cramps 
of  the  whole  body.  Dastre  removed  the  pitui- 
tary, but  the  animals  did  not  survive  the  opera- 
tion.    Gley  also  removed  the  hypophj^sis. 

Marinesco  operated  on  cats,  which  lived  from 
one  to  eighteen  days.  The  result  was  a  great 
amount  of  wasting  of  the  body,  although  arti- 
ficially fed. 

Vassale  and  Sacchi^  operated  on  dogs  and 
cats,  and  the  longest  time  they  lived  was  four- 

1  Rivisia  sperim  di  Freniatria,  XVIII,  1892.     Ibid..  XX,  1894. 


66 

teen  days.  The  symptoms  mere  apathy,  motor 
troubles,  rigidity  of  the  back,  somnolence, 
vacillating  gait,  dyspnea,  anorexia,  and  polyuria. 
The  dogs  also  rapidly  lost  flesh,  and  had  tonic 
and  clonic  cramps  with  fibrillary  contractions. 
Injection  of  pituitary  extract  temporarily  made 
the  symptoms  better.  The  constant  low  tem- 
perature was  marked,  but  after  the  injection 
of  pituitary  extract  it  returned  to  normal. 
After  the  effect  of  the  injection  had  passed  off, 
the  temperature  sank  and  at  the  same  time 
the  general  state  was  worse.  Caselli  operated 
on  56  dogs  and  cats,  producing  extirpation, 
and  came  to  the  conclusion  that  the  pituitary 
was  a  helping  organ  to  the  thyroid.  The  opera- 
tions were  made  through  the  mouth,  boring 
through  the  base  of  the  skull.  The  hypophysis 
was  destroyed  by  a  sharp  spoon,  thermocautery 
or  through  chemicals. 

Caselli  found  that  complete  removal  of  the 
functions  of  the  pituitary  caused  at  first  slow- 
ing of  respiration,  acceleration  of  pulse,  then 
depression  of  the  psychical  faculties,  motor 
troubles  with  curving  of  the  spine,  spastic  gait 
without  tonic  or  clonic  contractions,  convul- 
sive attacks,  progressive  cachexia,  coma  and 
death.  In  partial  lesion  of  the  hypophysis, 
in  adults,  you  have  the  same  symptoms  as  after 
total  ablation,  but  these  symptoms,  correspond- 
ing to  the  functional  insufficiency,  gradually 
disappear  and  the  animal  passes  into  a  sub- 
normal   state   compatible    with   life.     Psychical 


67 

depression  persists.  In  animals  which  are  grow- 
ing, the  functional  arrest  of  the  hypophysis 
prevents  their  normal  growth.  The  extirpa- 
tion of  the  hypophysis  modifies  the  course  of 
tetania  parathyreopriva,  the  tetany  ceases 
after  a  short  time  and  paralysis  ensues,  followed 
by  coma  and  death  in  forty-eight  hours.  ^ 

Friedman  and  Maas  arrived  at  the  conclusion 
that  total  extirpation  of  the  pituitary  was 
not  incompatible  with  life.  Monaco  and  Van 
Rynberk  arrived  at  the  same  conclusion.  Pir- 
one  operated  on  dogs,  making  partial  and  total 
hypophysectomies,  and  considered  that  the 
motor  troubles,  the  apathy,  psychic  depression, 
rapid  wasting,  cachexia  and  death  were  due 
to  pituitary  insufficiency.  He  made  some  urinary 
analyses  on  the  operated  animals,  and  found 
an  augmentation  of  urea  and  extractives.  Gatta 
made  some  experiments  and  arrived  at  the  con- 
clusion that  the  hypophysis  is  indispensable 
to  life. 

Paulesco^  arrived  at  the  gland  by  means 
more  adequate  to  remove  the  entire  gland  than 
previous  observers  who  probably  did  not  re- 
move the  whole  gland  as  they  operated  either 
by  way  of  the  base  of  the  skull  or  by  the  vertex. 
Paulesco  freely  removed  the  temporal  bone 
on  both  sides,  incised  the  dura  mater,  then 
he  elevated  the  brain  on  one  side  by  a  retractor 
until    the    reddish    yellow    pituitary    was    seen 

>  Casein,  Studi    anatomici    esperimentale  sulla    Fisiopathologia 
Delia  Glandola  piluitaria,  1900. 

2  L'Hypophyse  du  cerveau,  1908. 


68 

lying  in  the  sella  turcica.  Then  it  can  by  a 
small  curette  be  easily  shelled  out,  and  the 
brain  restored  to  its  normal  position  and  the 
wound  closed.  On  the  first  day  after  the  opera- 
tion the  animal  had  no  bad  symptoms,  but  on 
the  second  day  they  showed  lassitude  and  died 
without  any  clear  reason. 

Paulesco  states  that  the  mere  separation  of 
the  pars  nervosa  from  the  infundibulum  has 
sometimes  proved  as  quickly  fatal  as  the  actual 
removal  of  the  gland. 

Fichera  (1906)  and  Gemelli^  state  that  re- 
moval of  the  hypophysis  is  not  followed  by  a 
fatal  result.  It  is  probable  that  they  did  not 
remove  the  whole  gland,  or  the  few  cells  in  the 
pharyngeal  pituitary  of  Haberfeld  compensated. 

Masay-  has  tried  to  produce  pituitary  insuffi- 
ciency, that  is,  a  lessening  of  the  functions  of 
the  gland  by  preparing  an  anti-serum  by  intra- 
peritoneal injection  of  a  guinea  pig  with  an 
emulsion  of  a  dog's  pituitary  at  intervals  of 
two  days.  After  five  injections  he  collected 
the  blood  of  the  guinea  pig,  centrifugalized  it 
and  injected  the  serum  (about  10  cc.)  subcu- 
taneously  in  the  dog.  After  two  or  three  of 
such  injections  the  dogs  lost  flesh,  had  muscular 
weakness,  especially  of  the  posterior  extremities, 
also  changes  in  the  skeleton  and  histological 
changes  in  the  pituitary  from  a  true  cachexia 
hypophysipriva. 

'  Folio  Neuro-Biologica.  Nov.,  1908.  p.  167. 
'^  L'Hypophyse,    1908. 


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69 

Cyon^  holds  that  the  pituitary  gland  contains 
several  substances,  one  of  which  acts  on  the 
vagus,  increasing  its  force  and  slowing  its  rate, 
acting  like  muscarine.  He  also  saw  the  rise 
of  blood  pressure.  His  results  have  been  con- 
tradicted by  several  observers.  An  antitoxic 
function  of  the  hypophysis  has  been  ascribed 
to  it  by  Guerrini,  Gemelli  and  Thaon. 

Narbut  (1909)  in  Bechterew's  laboratory  found 
on  extirpation  of  the  hypophysis  a  fall  of  tem- 
perature on  the  day  of  operation,  which  he  thinks 
was  probably  due  to  injury  of  the  tuber  cinereum. 
Dr.  Sakovic  has  shown  that  lesion  of  the  tuber 
reduces  the  temperature.  Narbut  noted  a  marked 
sinking  of  the  temperature  before  death  (Fig. 
11).  He  also  noted  after  removal  of  the  pituitary 
an  arrest  of  growth  in  the  anterior  and  posterior 
extremities  and  a  partial  want  of  growth  in 
the  skull. 

The  excretion  of  phosphorus  and  nitrogen 
was  increased  both  absolutely  and  relatively, 
the  excretion  of  the  phosphates  being  increased 
threefold.  The  oxygen  consumption  and  the 
CO2  exhalation  was  decreased.  The  water  ex- 
haled was  decreased  (Figs.  11  and  12).^ 

Gushing,  Crowe  and  Homans  found  that  Ge- 
melli's  results  were  due  to  an  incomplete  re- 
moval of  the  gland.  Gushing  found  that  young 
animals,  puppies,  after  hypophysectomy,  do 
not  have  cachexia  hypophyseopriva  until  thirty- 

1  Die  Gefdssdrusen,  1910. 

'  Bechterew,    Die  Funktionen   der   Nervencentra,  Zweites  Heft, 
1909,  p.  1219. 


70 

six  hours  to  two  weeks  or  so  after  the  operation; 
with  a  transient  glycosuria,  with  or  without 
polyuria,  the  animal  is  norrnal  in  appearance. 
Then  inactivity  with  a  little  stiffness  and  un- 
steadiness of  gait  is  seen,  lower  temperature, 
awkward  arching  of  back  with  incurvation  of 
tail.  There  is  a  slow  pulse  and  respiration, 
irregular  muscular  contraction,  often  snapping 
of  the  jaws,  coarse  shivering  movements  like 
in  tetany.  The  animal  is  lethargic,  indiiferefit 
to  his  surroundings,  becomes  comatose,  slow 
pulse  and  occasional  diaphragmatic  respiratory 
movement.  The  temperature  falls  to  20°  C, 
or  lower. 

In  the  hypophysectomized  animals  there  were 
striking  changes  in  thyroid  and  testis. 

In  the  removal  of  the  pars  posterior,  although 
some  fragments  of  pars  intermedia  are  left, 
there  is  no  post-operative  alteration  in  blood 
pressure,  or  in  urinary  secretion.  In  partial 
removal  of  the  anterior  lobe,  the  animals  re- 
main undersized,  acquire  no  secondary  sexual 
characteristics,  have  a  tendency  to  hypotrichosis, 
and  have  subnormal  temperature.  In  several 
adult  males  after  a  partial  hypophysectomy  of  the 
anterior  part  there  is  a  loss  of  spermatozoa, 
absence  of  mitosis  and  other  peculiar  changes 
in  the  spermatogenetic  epithelium  and  cer- 
tain alterations  in  the  interstitial  cells  of  Leydig. 
Histological  changes  are  seen  in  the  islets  of 
L-angerhans.  ^ 

1  Am.  Journal  of  Medical  Sciences,  April,  1910,  p.  473. 


71 

Crowe,  Gushing  and  Homans^  confirni  Paules- 
co's  work,  that  the  pars  anterior  of  the  hypophy- 
sis is  necessary  to  life.  They  show  that 
Von  Cyon's  views  (previously  contradicted) 
are  incorrect  about  the  effect  of  mechanical 
irritation  of  the  pituitary  affecting  the  circula- 
tion or  respiration.  They  observed  no  effect. 
Removal  of  posterior  lobe  produces  no  cachexia 
hypophyseopriva.  Separation  of  the  hypophy- 
seal stalk,  owing  to  circulatory  disturbances, 
is  comparable  either  to  a  partial  hypophysec- 
tomy  or  to  a  total  removal  with  immediate 
reimplantation  of  the  excised  tissue  elsewhere 
in  the  body.  The  gland  becomes  reattached 
and  the  pathways  for  posterior  lobe  secretion 
supposed  to  traverse  the  pars  nervosa  on  its 
way  to  the  infundibular  cavity  may  become 
obstructed  by  the  scar  leading  to  an  accumula- 
tion of  hyaline  material  within  the  channels 
of  the  pars  nervosa.  We  have  seen  destruction 
of  the  pars  anterior  in  the  monkey  produce  death 
in  4  days. 

Injections  of  Pituitary. — Intraperitoneal  in- 
jection of  extracts  of  the  hypophysis  according 
to  Delille  acts  as  follows:  In  small  doses  the 
repetition  of  injections  for  3  to  4  days  causes 
congestion  and  hyperactivity  of  the  pituitary, 
the  eosinophile  cells  are  very  much  greater, 
the  extra-cellular  colloid  was  abundant.  After 
10  to  15  injections  the  eosinophile  cells  are 
less,    the   basophiles   relatively    abundant,   little 

I  Johns  Hopkitu  Bulletin,  p.  127.  May,  1910, 


72 

extracellular  colloid  and  a  considerable  quantity 
of  chromophobes,  there  is  no  congestion.  These 
facts  have  been  confirmed  in  the  main  by  Hal- 
lion,  Alquier  and  Guerrini.  Under  the  influence 
of  injections  of  the  whole  hypophysis  the  adrenals 
double  in  weight,  there  is  a  diffuse  cortical 
hyperplasia.  The  intraperitoneal  injections  seem 
to  stimulate  the  adrenal  secretion.  The  pituitary 
injections  cause  remarkable  changes  in  the 
thyroid  which  is  poor  in  large  vesicles;  there 
is  little  colloid,  which  finally  disappears.  At 
the  periphery  of  the  thyroid  the  large  vesicles 
are  nearly  empty.  The  injections  produced  no 
effect  upon  the  ovary  or  testis  of  a  rabbit  treated 
for  more  than  a  year.  She  was  able  to  fecundate. 
In  small  doses  it  produces  slight  congestion 
of  the  liver  and  a  granular  fatty  degeneration 
at  the  peripher}^  of  the  lobule.  The  spleen 
did  not  show  any  changes.  The  kidneys  were 
slightly  congested;  the  glomerulus  was  always 
increased  in  size. 

Extracts  of  the  posterior  lobes  cause  the 
same  results  as  the  whole  gland.  Extracts 
of  the  anterior  lobe  cause  a  slight  hyperactivity 
of  the  hypophysis  and  do  not  change  the  adrenals. 
The  thyroid  by  injection  of  the  pars  anterior 
shows  a  state  of  hyperfunction,  the  colloid  is 
very  abundant,  and  the  large  vesicles  are  very 
numerous.  The  anterior  part  causes  the  same 
lesions  as  the  whole  gland,  but  the  lesions  are 
less  marked.  The  spleen  is  a  little  congested. 
The  islets   of    Langerhan's    are   also    congested. 


73 

Parhon  and  Golstein  found  the  following  changes 
by  the  injection  of  the  hypophysis:  thyroid 
nornial,  atrophied  seminiferous  tubules;  no 
change  in  ovary,  adrenals  enlarged  and  in 
a  state  of  hyperplasia,  fatty  liver,  spleen  norraal, 
and  parenchymatous  lesions  of  the  kidneys. 

G.  Franchini^  arrived  at  the  conclusion  from 
numerous  experiments. 

(i)  The  extract  in  rabbits  only  exception- 
ally causes  glycosuria. 

(2)  The  extract  of  the  hypophysis  causes, 
besides  a  toxic  action,  on  rabbits  and  guinea 
pigs,  an  especial  action  upon  the  intestinal 
canal  producing  ulceration  and  hemorrhages. 

(3)  The  greatest  toxic  activity  is  by  the 
vein,  but  it  can  also  ensue  by  subcutaneous 
or  gastric  exhibition.  The  act  of  digestion  in 
vitro  partly  weakens  the  toxic  action. 

(4)  The  glandular  part  isolated  from  the 
pars  intermedia  produces  only  slight  disturb- 
ances. If  the  pars  intermedia  is  combined  with 
it  then  it  is  toxic.  The  infundibular  part  iso- 
lated from  the  pars  intermedia  has  an  especial  ac- 
tion upon  metabolism  and  an  action  upon  the 
blood  vessels  and  the  organs  of  abdomen  and 
the  pelvis. 

(5)  The  infundibular  part  isolated  from  pars 
intermedia  contains  a  substance  which  dilates 
the  frog's  pupil.  This  dilation  is  not  produced 
by  the  anterior  lobes,  but  by  the  pars  inter- 
media and  in  a  much  less  degree  than  by  the 

1  Berliner  Klinisch-e  Wochenschrift,  1910,  p.  723. 


74 

infundibular  part.  The  serum  from  animals 
who  have  received  injections  from  the  extract 
of  the  posterior  lobe  produces  dilated  pupil. 
The  serum  from  animals  injected  with  extract 
of  the  isolated  anterior  glandular  part  isolated 
from  the  pars  intermedia  very  seldom  causes 
dilation  of  pupil,  but  if  the  pars  intermedia 
is  combined  with  the  glandular  anterior  part 
the  dilation  of  pupil  is  more  frequent. 

Gushing,  Crowe  and  Homans^  found  after 
repeated  injections  of  the  posterior  or  infundib- 
ular lobe  that  there  was  loss  of  weight,  ex- 
treme degree  of  hepatic  degeneration  and 
necrosis,  subsequently  found  under  other  ex- 
perimental conditions.  This  same  lesion  with 
no  accompanying  histologic  changes  in  the 
kidneys  has  been  found  in  a  number  of  hypophy- 
sectomized  animals  ■without  injections. 

The  subcutaneous  administration  of  the  pars 
anterior  caused  no  such  disturbances  even  when 
given  daily  over  three  months.  Hence  Gush- 
ing used  the  pars  anterior  as  a  means  of  tiding 
over  periods  of  threatened  cachexia  hypophyseo- 
priva  in  cases  of  almost  total  hypophysectomy. 
He  also  used  the  pars  anterior  to  produce  hyper- 
pituitarism. 

Action  of  Pituitary  on  Metabolism. — Malcolm^ 
studied  the  action  of  the  pituitary  on  the  ex- 
cretion of  inorganic  substances. 

Nitrogen. — The    dried     glandular    portion    of 

'  Bulletin  Johns  Hopkins,  May,  1910. 

2  Jotirnal  of  Physiology.  Vol.  XXX.   1904,  p.  270. 


75 

the  pituitary  orally  caused  a  slight  retention 
of  nitrogen;  the  dried  nervous  portion  had  a 
similar  effect.  The  fresh  entire  gland  increased 
the  output  of  nitrogen. 

Phosphorus. — The  glandular  portion  caused 
a  retention  of  phosphorus,  while  the  nervous 
part  caused  a  loss  followed  by  a  retention. 

Calcium  and  Magnesium. — Both  dried  gland- 
ular and  dried  nervous  part  increased  the 
output  of  calcium  (on  a  calcium-rich  diet) ; 
while  the  excretion  of  calcium  in  the  glandular 
case  was  accompanied  by  an  increased  output 
of  magnesium  (in  the  feces  at  any  rate),  the 
nervous  was  not,  or  not  to  the  same  extent,  so 
accompanied.  This  points  to  the  nervous  por- 
tion having  a  katabolic  action  on  the  bony 
tissues. 

Thompson  and  Johnston^  found  the  injec- 
tion of  the  entire  pituitary  to  lead  to  loss  of 
weight  by  stimulating  metabolism,  increasing 
the  nitrogen,  urea  and  phosphorus  in  the  urine. 

Sandri  observed  no  effect  upon  the  growth 
of  young  mice  from  a  two  months'  feeding  of 
the  pars  anterior  of  beef  pituitary,  while  those 
fed  with  posterior  lobe  showed  a  notable  arrest 
of  development. 

Gushing  states  that  repeated  daily  injections 
over  long  periods  of  the  pars  posterior  leads 
to  progressive  emaciation,  often  with  marked 
degenerative  changes  in  the  spleen  and  central 
necroses  in  the  liver.     Similar  results  of  auto- 

^  Journal  of  Physiology.  1905,  p.  889. 


76 

intoxication  were  not  uncommonly  seen  after 
operative  removal  of  the  gland. 

Repeated  daily  hypodermic  injections  of  the 
anterior  lobe  caused  loss  of  weight,  which  has 
been  seen  by  Casselli  and  others. 

H.  Salomon  by  feeding  healthy  men.  with 
large  quantities  of  pituitary  tablets  found  no 
increase  of  the  respiratory  gases. 

Franchini^  noted  great  changes  by  pituitary 
in  metabolism,  especially  in  the  inorganic  part. 
There  is  a  great  deficiency  of  calcium  and  mag- 
nesium and,  to  a  small  degree,  also  of  phos- 
phorus in  the  body.  In  the  circulating  blood, 
however,  there  is  an  increase  of  calcium  and 
magnesium. 

Metabolism  in  Acromegaly. — A.  Schiflf,  of 
Vienna,  found  that  the  giving  of  hypophysis  to 
an  acromegalic  caused  a  slight  increase  of  nitrogen 
excretion;  the  quantity  of  phosphorus,  especially 
by  the  intestine,   was  increased. 

We  may  conclude  that  pituitary  decreases  the 
phosphates  in  the  urine  and  increases  them  in 
the  fecal  matter.  Infundibulin  increases  the 
excretion  of  calcium  by  the  intestine  and  of 
magnesium  by  the  urine.  The  nitrogen  excreted 
is  increased. 

Magnus  Levy  in  a  case  of  acromegaly  found 
that  pituitary  did  not  increase  metabolism  at 
all,  or  not  to  any  important  extent. 

Parhon^  has  observed  in  acromegaly  that 
tablets  of  pituitary  caused  an  augmentation  of 

1  Berlin  Klin.  Woch.,  1910,  p.  723. 

2  Presbeanu,  These,  1909. 


77 

the  phosphates  and  a  retention  of  calcium  salts. 

Tauzk  and  Vas  examined  the  excreta  and 
injecta  for  8  days  of  an  acromegalic  and  showed 
that  the  weight  of  the  body  augmented.  Nitrogen 
and  phosphorus  were  less  in  the  excreta,  while 
the  salts  of  calcium  were  eliminated  in  more  con- 
siderable quantity  compared  with  those  injected. 

Moraczewski  found  in  a  case  of  acromegaly  a 
retention  of  chlorine,  nitrogen,  phosphorus  and 
salts  of  calcium.  Audenino  in  studying  two 
cases  of  acromegaly  found  in  the  first  period  a 
loss  of  nitrogen,  which  disappeared  later.  There 
was  also  an  increase  in  the  earthy  phosphates. 
In  the  one  case  calcium  was  retained,  in  the 
other  eliminated  in  a  great  degree. 

Parhon  from  an  analysis  of  urine  in  acromegaly 
found  a  constant  retention  of  phosphorus,  the 
urea  often  diminished. 

The  eHmination  of  phosphoric  acid  was 
diminished. 

Franchini  studied  three  cases  of  acromegaly. 
He  found  in  one  a  retention  of  N  and  CaO  and 
MgO  and  a  loss  of  PjOj,  and  a  less  marked  re- 
tention of  CI.  In  the  second  case  he  noted  a 
retention  of  N  and  CI  and  a  loss  of  the  three  other 
bodies.  He  noted  an  augmentation  of  elimina- 
tion of  calcium  by  the  urine  and  a  decrease  of 
its  eUmination  by  the  intestine. 

Miller  and  Kds^U  found  in  acromegaly  a 
marked  retention  of  N,  phosphorus  and  calcium. 

1  Medical  News,  1903. 


78 

Parhon  cites  Silva  who  observed  in  acromegaly 
a  marked  retention  of  nitrogen,  increased  elimina- 
tion of  sulphates  and  chlorides,  while  the  phos- 
phates were  nearly  normal. 

It  can  be  inferred  from  a  study  of  the  urinar}^ 
excretions  of  acromegalics  and  when  pituitary 
is  given  to  them,  that  the  excretion  of  nitrogen 
is  less,  that  the  phosphates  are  sometirhes  in- 
creased, at  other  times  decreased,  that  calcium 
in  the  majority  of  cases  is  less,  although  in  some 
experiments  there  was  an  increase  of  calcium  in 
the  urine,  and  a  decrease  of  it  by  the  intestines. 

Growth. — Shafer  has  made  some  experiments 
with  white  rats,  feeding  them  with  powdered 
anterior  lobe  of  the  pituitary,  then  weighing 
them  and  comparing  their  weight  with  that  of 
control  rats  of  the  same  litter.  There  seemed 
to  be  an  increase  of  weight  in  those  fed  with  the 
anterior  part  of  the  pituitary. 

We  have  observed  a  great  loss  of  weight  in 
rabbits  by  subcutaneous  injection  of  the  hy- 
pophysis when  continued  for  a  few  weeks. 
Gushing  has  also  observed  a  loss  of  weight  by 
the  injection  of  the  whole  pituitary  or  of  the 
infundibular  lobe  alone. 

Schafer^  thinks  the  pars  anterior  is  probably 
related  to  the  growth  of  the  cartilages, 
bones,  and  connective  tissue  in  general,  due  to 
hormones.  The  function  of  the  pars  intermedia 
is  to  produce  a  colloid  material  which  contains 

•  Croonian  Lecture,  Proceedings  of  the  Royal  Society,   B.  Vol. 
81.  1909.      "Functions  of  the  Pituitary  Body." 


79 

the  active  principle  acting  upon  heart,  blood 
vessels  and  kidney. 

Aschner  has  removed  the  hypophysis  in  a 
young  dog  and  compared  it  with  a  dog  of  the 
same  brood.  The  dog  without  the  hypophysis 
was  stunted  in  growth.  He  holds  that  the  hy- 
pophysis is  not  necessary  to  life  and  that  its 
absence  produces  dwarfs.  This  is  supported 
by  post-mortems  in  the  case  of  dwarfs.^ 

Relation  between  the  Glatids. — Fichera  found 
after  castration  in  roosters  that  the  weight  of 
the  anterior  part  of  the  pituitary  doubled  with 
an  increase  of  eosinophile  cells.  This  also  held 
good  for  rabbits  and  oxen.  Marenghi  found  after 
extirpation  of  the  adrenals  in  cats  and  rabbits 
an  increase  of  the  pituitary.  Rogowitsch  found 
a  hypertrophy  of  the  pituitary  after  removal 
of  the  thyroids.  This  has  been  confirmed  by 
numerous  observers,  as  Hofmeister,  Comte, 
Herring   and    others.^ 

In  castrates,  the  hypophysis  is  enlarged,  as 
has  been  shown  by  Fichera,  Cimoroni,  Tandler 
and  Gross.  This  hypertrophy  is  due  to  an 
enormous  increase  of  the  chromophile  cells 
which  are  a  Uttle'^  larger  than  the  normal  ones. 

Comte,  Mulon,  Von  Erdheim  and  Stumme 
have  shown  the  changes  in  pituitary  during 
pregnancy  while  in  acromegaly  there  are  changes 
in  the  genitaUa.  The  thyroid  when  ablated 
produces  an  arrest  in  the  growth  of  the  bones. 

1  Wiener  Klinische  Wochenschrift,  p.  572,  1910. 

2  Oppenheim's  Handbuch  der  Bio-Chemie,  Band  3,  erste  Halfte. 
p.  342. 


8o 

Hinsdale  examined  the  records  of  57  cases  of 
autopsies  of  acromegalics;  15  times  the  thyroid 
was  enlarged,  11  times  it  was  atrophied,  and  12 
times  it  was  normal. 

The  persistence  of  the  thymus  has  been  noted 
many  times  in  the  autopsies  of  acromegalics. 
The  thymus  and  the  chromaffine  tissue  also 
have  a  relation  to  the  genital  glands. 

In  myxedema  and  cretinism  the  hypophysis 
is  enlarged,  as  has  been  shown  by  Ponfick, 
Dolega  and  others. 

Parhon  and  Golstein  and  Pepere  found  that 
extirpation  of  the  parathyroids  had  an  influence 
upon  the  hypophysis  which  enlarges  and  the 
chromophiles  are  very  numerous  (Fig   13). 

Is  Acromegaly  a  Hyperhypophysy'? — Pierre 
Marie  first  pointed  out  that  in  acromegaly  you 
have  a  disease  of  the  pituitary  and  held  it  was 
due  to  a  hypohypophysy.  Tamburni  and  Benda 
beUeved  it  was  hyperhypophysy,  an  excess  of 
chromophile  cells  being  present.  Hochnegg, 
in  a  case  of  acromegaly  which  was  the  first  case 
successfully  operated  on  (1908),  showed  that  a 
year  after  the  operation  the  length  of  the  fingers 
and  the  feet  diminished.  Here  we  have  in  man 
(as  Alfred  Exner  has  stated)  a  decrease 
where  an  operation  produced  hypohypophysy, 
which  reduced  the  acromegalic  hands  and  feet. 

Since  Hochnegg's  first  successful  case  of 
hypophysectomy  for  acromegaly,  he  has  operated 
on  two  other  acromegalics,  and  one  of  these 
showed    a    great    similarity    to   the    first  case. 


Fig.  13. — A  case  of  acromegaly  (Bouchard). 


8i 

The  menses  which  had  stopped  for  seven 
years  returned.  An  adenomatous  tumor  was 
removed,  the  great  increase  of  pain  present 
diminished,  and  the  fat  decreased.  The  hands 
and  feet  diminished  in  size.  The  third  case 
was  a  woman  thirty-four  years  old;  her  menses 
had  stopped  for  three  and  one-half  years,  and 
she  had  marked  symptoms  of  acromegaly. 
She  died  shortly  after  the  operation.  All  three 
cases  were  adenomatous  tumors.^ 

The  enlargement-  of  the  pituitary  during 
pregnancy  means  an  hyperhypophysy,  and  a 
diminished  function  of  the  internal  secretion  of 
the  ovaries.  In  both  cases  of  recovery  after  Hoch- 
negg's  operation  there  was  marked  enlargement 
of  the  thyroid.  Gushing  observed  a  simular 
effect   after   a   hypophysectomy   in   man. 

The  operation  of  Hochnegg's  was  the  first 
experimental  evidence  in  man  to  prove  that 
acromegaly  was  due  to  a  hyperhypophysy  and 
not  to  hypohypophysy  as  held  by  Marie. 

Gushing  removed  a  part  of  the  anterior  lobe 
in  man,  and  a  post-operative  reduction  in  the 
hands  ensued.  There  are,  however,  cases  of 
acromegaly  without  enlargement  of  the  hy- 
pophysis, but  minute  changes  in  the  h3TDophysis 
might  be  overlooked,  or  even  small  tumors,  as 
in  a  case  of  Erdheim's,  where  with  a  normal 
hypophysis  a  small  tumor  was  found  beneath 
the  sella  completely  separated  from  the  pituitary. 

1  Miiieilungen   aus  den   Grenzgebieten   der   Med.  und   Chirurg., 
1909,  p.  620. 


82 

Brissaud  and  Henry  Meige  were  the  first  to 
conclude  that  giantism  and  acromegaly  are  the 
same  disease.  The  appearance  in  youth  is 
giantism  and  in  the  adult  it  is  acromegaly. 
The  age  is  the  only  difference.  Halmagrand 
(1907)  holds  that  hyperhypophysy  causes 
giantism. 

Launois  and  Roy  (1904)  hold  that  giantism 
corresponds  to  a  hyperacti\dty  of  the  pituitary 
before  the  union  of  the  epiphyses  and  acromegaly 
to  the  same  hyperactivity  after  the  union  of  the 
epiphyses.  Gushing  states  that  hyperpituitarism 
in  youth  gives  giantism;  in  adult  life  it  is 
acromegaly.  ^ 

Sternberg  arrived  at  the  conclusion  that  in 
acromegaly  it  was  chiefly  the  anterior  part  of 
the  pituitary  which  was  the  constant  seat  of 
the  lesions.  A  histological  study  of  a  series 
of  tumors  of  the  hypophysis  has  a  common 
mark,  an  increase  of  the  chromophile  cells, 
cells  which  are  supposed  to  be  secretory  cells. 
Hence,  Borchardt  arrived  at  the  conclusion  that 
there  is  a  hyperfunction  of  the  secretory  elements 
of  the  anterior  part  of  the  hypophysis,  as  the 
cause  of  acromegaly,  as  Hanseman  first  stated, 
and  later  Tamburini,  Woods  Hutchinson,  Gubler 
and  Benda.  Cagnetto  found  an  increase  of 
chromophile  cells,  as  did  Achard,  Loeper  and 
Lewis.  Cagnetto  in  a  case  of  tumor  of  the 
hypophysis  without  acromegaly  found  there 
was  an  absence  of  the  chromophile  cells  in  the 

'  Journal  Am.  Med.  Association,  July,  1909,  p.  255. 


83 

anterior  part  of  hypophysis.  The  same  was 
true  in  a  case  of  Carbone.  Hence  we  may  infer 
that  giantism  and  acromegaly  are  due  to  hyper- 
hypophysy  of  the  anterior  lobe  of  the  hypophysis 
and  to  a  hypersecretion  by  the  chromophile 
cells  of  the  pars  anterior. 

If  the  posterior  lobe  is  also  diseased  you  have 
polyuria.  We  might  add  that  glycosuria  is 
due  to  the  invasion  of  the  posterior  lobe  by 
disease  which  is  usually  cancer  or  sarcoma. 

Infantilism. — Meige's  definition  of  infantilism 
is  an  anomaly  of  development  characterized  by 
the  persistence  in  a  subject  having  attained  or 
passed  the  stage  of  puberty,  of  morphological 
characters  belonging  to  an  infant. 

Marie  believed  that  changes  in  the  functions 
of  the  sexual  glands  were  initial  symptoms  in 
acromegaly.  A.  Exner  believes  hyperhypophysy 
secondarily  leads  to  loss  of  function  of  the  sexual 
organs  and  amenorrhea.  When  the  pituitary 
was  removed  in  cases  of  tumor  then  the  menses 
became  regular. 

The  observations  of  skeletons  of  eunuchs  by 
Lortet,  by  Ecker  and  by  Pirsche  show  that  human 
castrates  have  a  retard  of  complete  ossification 
of  the  long  bones. 

Sellheim,  Bonnet,  Becker,  Poncet,  Pirsche 
and  Mobius,  in  the  lower  animals  after  castra- 
tion, have  shown  the  presence  of  active  cartilages 
in  the  long  bones  of  the  extremities  and  par- 
ticularly at  the  epiphyses,  which  normally  are 
joined  to  the  diaphyses.     This  fact  explains  the 


84 

unequal  development  of  the  extremities  in 
relation  to  the  trunk,  and  also  the  unequal 
development  of  difTerent  parts  of  the  extremities 
when  compared  among  themselves. 

Delille^  ascribes  hypohypophysy  as  the  cause  of 
pituitary  obesity,  associated  with  infantilism. 
He  also  makes  an  obesity  due  to  a  hyperhy- 
pophysy,  which  conduces  to  emaciation  by  the 
hyperhypophysy,  and  causes  hypothyroidism 
and  suppression  of  the  activity  of  the  sexual 
organs  and  thus  indirectly  produces  obesity. 
Here  we  have  a  pluri  glandular  action  con- 
cerned in  the  production  of  obesity.  The 
bone  changes,  the  obesity,  hypertension  in 
arteries,  and  polyuria  are  due  to  hyperhypophysy. 

Alfred  Exner  and  V.  Gschmeidler  have  grafted 
several  hypophyses  into  animals  and  found 
afterwards  a  very  marked  increase  of  fat  in 
them    compared    with    the    ungrafted    controls. 

Tandler  and  Gross  in  cases  of  acromegaly 
found  changes  in  the  epithelium  of  the  semenif- 
erous  tubules  and  in  the  interstitial  cells  of  the 
testis  and  ovary.  A.  Exner  remarks  that  it 
is  difficult  to  state  if  the  increased  amount 
of  hair  and  obesity  is  directly  due  to  hyper- 
hypophysy or  is  indirectly  due  to  the  hyper- 
hypophysy action  upon  the  interstitial  cells 
of  the  testis  and  ovary,  and  in  this  way  causing 
obesity  and  increased  amount  of  hair.  At  the 
menopause  when  the  ovarian  interstitial  tissue 
is  lowered  in  function  we  have  a  beard  develop, 

1  These  pour  le  Doctorat,  May  13,  1909. 


85 

and  there  is  a  more  abundant  growth  of  hair 
about  the  Hnea  alba. 

During  pregnancy  we  have  more  hair  in  the  same 
places  and  also  in  the  majority  of  cases  of  obesity. 
We  know  that  in  pregnancy  we  have  hyper- 
hypophysy.  In  the  acromegalic  after  the  re- 
moval of  the  swollen  hypophysis,  the  absent 
menses  return  and  impotency  is  lost.  Here  the 
interstitial  cells  of  the  sexual  glands  have  an 
inhibition  removed  and  recover  their  wonted 
activity.  Hence  A.  Kxner  holds  that  the  function 
of  the  ovary  and  testis  is  partly  to  regulate 
the  sexual  activity,  the  growth  of  hair  and 
obesity  and  that  this  function  is  inhibited  by 
increased  activity  of  the  pituitary. 

The  anterior  part  of  the  pituitary  seems  to 
be  associated  with  growth  of  the  body  with  fat 
metabolism,  and  sexual  activity.  Removal  of  the 
posterior  lobe  causes  no  apparent  disturbance 
of  the  physiological  balance  of  the  body. 

Boyce  and  Beadles,  in  a  woman  with  a  great 
amount  of  subcutaneous  and  peritoneal  fat, 
weighing  84  kilograms,  had  a  hypophysis  nearly 
double  in  size  and  the  augmentation  of  volume 
was  only  in  the  anterior  lobe. 

FrohUch  first  spoke  of  a  dystrophia  adiposo- 
genitalis,  where  we  have  infantilism  of  the  sexual 
apparatus  accompanied  with  obesity.  These 
patients  are  small  in  height,  have  a  smaller 
amount  of  hair,  and  excessive  obesity,  with  symp- 
toms of  pressure  in  the  vicinity  of  the  hypophysis. 

Von  Eiselsberg  has  operated  on  these  cases 


86 

described  by  Frohlich  where  they  had  pituitary 
disease  without  acromegaly,  removing  a  part 
of  the  hypophysis.  After  the  operation  the 
fat  diminished,  the  sexual  apparatus  was  aroused 
to  awakened  activity. 

Gushing  reports  a  case  of  a  man  aged  40  who 
became  very  fat  with  polyuria  and  transient 
glycosuria,  with  sub-normal  temperature,  slow 
pulse,  who  had  on  post-mortem  a  primary  tubercle 
of  the  hypophysis. 

Leman  and  Van  Wart^  reported  a  case  of 
infantilism  with  an  absence  of  the  thyroid  and 
a  tumor  of  the  hypophysis.  The  woman  was 
white,  her  skeleton  long.  No  axillary  or 
pubic  hair,  no  mammary  development,  uterus 
infantile,  lack  of  ossification  in  the  epiphyses, 
and  X-rays  showed  an  enlargement  of  the 
sella  turcica.  She  was  fed  with  thyroid  but 
without  benefit.  Pituitary  extract  improved 
her,  and  she  gained  15  pounds  in  weight,  a  pound 
per  week. 

Crowe,  Cushing  and  Romans^  have  found 
that  in  dogs  partial  removal  of  the  anterior 
lobe  of  the  pituitary  leads  to  a  state  of 
adiposity  accompanied  by  a  secondary  hypo- 
plasia of  the  organs  of  generation  in  adults 
or  by  a  persistence  of  sexual  infantilism  in  case 
the  primary  hypophyseal  deficiency  antedates 
adolescence.  Polyuria,  glycosuria,  alterations  in 
the  skin  and  its  appendages   (such    as    edemas 

1  Archives  of  Internal  Medicine.  1910.  p.  519. 
^  J ohMs  Hopkins  Bulletin,  p.    127,   May,    1910. 


87 

and  hypotrichosis),  the  tendency  to  a  subnormal 
body  temperature  and  psychic  disturbances  are 
more  or  less  frequent  accompaniments,  all  of 
them  symptoms  which  occasionally  occur  with 
states  of  adiposity  and  of  sexual  infantilism 
in  man  in  company  with  certain  pituitary 
body-tumors,  states  therefore  which  presumably 
are  due  to  deficiency  of  the  pars  anterior. 

Gushing  and  his  co-workers  have  undoubtedly 
cleared  up  the  question  that  the  cases  of  infant- 
ilism with  excess  of  fat  and  atrophy  of  genitalia, 
are  due  to  hypopituitarism  of  the  pars  anterior. 
How  much  the  interstitial  cells  of  Leydig  .or 
the  interstitial  cells  of  the  ovary  according  to 
the  theory  of  Tandler  and  Gross  play  a  part 
in  infantilism  is  still  to  be  worked  out.  Gushing 
has  found  changes  in  the  Leydig  cells  of  the 
testes  of  the  dog. 

It  must  also  be  inferred  according  to  Aschner 
that  hypohypophysy  produces  dwarfs. 

Hence  cases  of  infantilism  may  be  divided 
into  two  classes:  (i)  due  to  direct  action  of 
hypohypophysy,  (2)  the  other  indirect  due  to  the 
hyperhypophysy,  action  on  the  thyroid  producing 
hypothyroidism  and  suppression  of  the  activity 
of  the  interstitial  cells  of  the  testis  or  ovary. 
These  are  the  cases  of  "pluriglandular  insuffi- 
ciency"  of  the  French,  authorities. 

Transplants. — Growe,  Gushing  and  Homans 
had  four  cases  in  dogs  of  total  hypophysectomy 
with  hypertrophic  changes  in  the  thyroid,  but 
where  rectus  implantation  of  the  pituitary  pro- 


88 

longed  the  life  of  the  animals.  In  another  dog 
they  implanted  in  a  cavity  prepared,  by  inserting 
a  silver  ball  in  bone  marrow  for  ten  days,^  and 
then  implanting  the  hypophysis  from  another 
dog.  Four  days  after  the  transplantation  the 
dog's  hypophysis  was  removed;  no  symtoms 
ensued  from  the  operation.  The  animal's  life 
was  prolonged  over  the  usual  period  of  three 
to  four  days  by  the  transplantation  of  hypophy- 
seal tissue.  In  an  auto-transplantation  into 
the  cortex  cerebri  after  a  total  h3'pophysectomy, 
the  duration  of  life  was  prolonged  for  eighteen 
days,  when  he  was  killed. 

Glandular  transplants  or  injections  of  anterior 
lobe  emulsions  definitely  prolong  the  life  of  ani- 
mals after  total  hypophysectomy  and  likewise 
tide  over  periods  of  threatened  cachexia  hy- 
pophyseopriva  in  animals  retaining  anterior 
lobe  fragments  which  temporarily  may  be 
physiologically  insufficient.  They  noted  in  some 
of  the  hypoph^'sectomies  a  marked  polyuria 
with  transplants  even  of  the  anterior  lobe  alone 
in  the  transplant.  This  pol3mria  disappears 
after  extirpation  of  the  transplant.^ 

A.  Exner-  has  implanted  hypophyses  in  young 
rats.  Their  weight  was  increased,  due  to  an 
augmented  length  in  part  and  to  increased  fat. 

Therapeutical  Application. 
Shock.     Intestinal  Paresis,  Uterine  Contraction. 
— Burroughs     Wellcome    &    Co's    infundibular 

'  Quarterly    Journal    Experiment^    Physiology,    389,     Vol.    II, 
No.  4,  1909. 

^  Zentralblatt  jiir  Physiologie,  Band  XXIV,  p.  387. 


extract  kept  the  blood,  pressure  in  man  elevated 
for  twelve  hours.  Bell  recommends  it  for  shock, 
like  Mummer}-,  Lockhart  and  Symes.^  This 
Wellcome  extract  of  the  infundibular  lobe  causes 
powerful  contractions  of  pregnant,  puerperal 
and  menstruating  uteri.  Bell  also  found  it 
had  a  marked  effect  upon  intestinal  muscle, 
and  found  it  useful  subcutaneously  into  the 
muscles  of  the  forearm  for  paresis  and  distension 
of  the  bowel  after  abdominal  operations.  The 
vaporole  extract  can  be  boiled  and  thus  steril- 
ized, but  must  be  injected  into  the  muscles  to 
avoid  superficial  sloughing  from  the  local  vaso- 
constriction. The  dose  may  be  repeated  with 
an  hour's  interval.  It  acts  better  on  paretic 
intestine  than  on  the  normal  one.- 

G.  G.  Wray^  has  treated  post-operative  shock 
with  considerable  success.  He  injected  i  cc. 
of  Burroughs  Wellcome  &  Go's.  20  per  cent,  infun- 
dibular extract  into  the  deltoid  muscle.  The 
effect  of  the  pituitary  extract  upon  the  small, 
feeble  pulse  was  to  make  it  large,  regular  and 
forceful.  Its  effect  lasted  about  twelve  to 
fifteen  hours. 

Dr.  J.  A.  Henton  White,  in  a  puerperal  case 
with  pneumonia  and  a  weak  heart,  used  12 
minims  of  pituitary  extract  by  injection  into 
the  buttocks  to  stop  post-partum  hemorrhage. 
The  depression  which  ergot  would  cause  was 
unsuitable   in   this   case.      The  pituitary  caused, 

1  British  Med.  Journal.  Vol.  H.  p.  736,  1908. 

2  BeU,  British  Medical  Journal,  p.  1609  Dec,  4,  1909. 

3  British  Medical  Journal,  1909,  p.  1745. 


90 

after  the  grasping  of  the  placenta,  a  violent 
contraction  of  the  uterus.  The  pulse  instead 
of  being  thready  and  uncountable  soon  acquired 
a  full  volume  and  good  tension.  The  general 
condition  was  very  good.^ 

Thumin  recommends  in  excessive  menstruation, 
due  to  ovarian  disturbance  or  excessive  desires 
dependent  upon  an  increased  activity  of  the  ovary 
as  in  nymphomania  and  other  psychoses,  tablets 
of  the  hypophysis.  It  is  known  that  the  ex- 
cessive secretion  in  acromegaly  causes  a  cessation 
of  menstruation  and  loss  of  sexual  desire.^ 

Tachycardia  and  Hypotension  in  Arteries. — ■ 
When  as  a  result  of  hypohypophysy  by  the  toxines 
of  diphtheria,  or  those  of  endogenous  origin, 
then  the  use  of  pituitary  is  of  great  value.  Hy- 
pertension is  an  absolute  contra-indication  to 
the  use  of  pituitary  extract.  In  the  use  of 
pituitary  you  watch  the  pulse  and  pressure  and 
also  examine  the  urine  and  blood. 

Delille  states  that  the  extracts  of  the  anterior 
lobe  do  not  produce  an  appreciable  therapeutic 
effect.  Delille  gives  each  day  o.io  gram  to 
0.40  gram  of  the  whole  dried  gland. 

Hallion  and  Carrion  have  seen  a  venous  in- 
jection of  pituitary  extract  in  the  dog  produce 
an  intense  vaso-constriction  of  the  thy- 
roid as  shown  by  the  plethysmograph.  This 
explains  the  good  effects  of  pituitary  medication 
in  Basedow's  disease.^ 

^British  Med.  Journal,  1910,  p.   1282. 

-  Berlin  Klinische  Wochenschrift,   1909,  p.  631. 

3  Halmagrand,  Etat.  Actuel  de  V Infantilism,  1907,  p.  58. 


91 

H.  Nageli  and  P.  Vernier,  of  Geneva,  have  used 
20-40  grams  of  powdered  hypophysis  extract 
with  good  results  in  low  arterial  tension. 

Which  Preparation  of  the  Pituitary  is  the  Best 
to  Use  in  Tetany? — We  have  shown^  in  feline 
tetany  that  the  pituitary  gland  given  in  distilled 
water  subcutaneously  had  an  effect  at  least 
equal  to  the  calcium  salts  in  alleviating  the 
tetany  after  complete  parathyroidectomy.  As 
calcium  has  failed  in  several  instances  to  cure 
tetany  in  man  it  is  necessary  to  seek  other 
agents  to  combat  the  disease. 

Professor  Pal,  of  Vienna,  reports^  a  case  of 
severe  tetany  in  a  boy.  He  gave  pituitrin  and 
the  tetany  disappeared  in  twenty-four  hours, 
while  the  other  symptoms  retrograded.  We 
have  made  experiments  with  pituitrin  in  feline 
tetany  and  find  it  has  some  effect  which  is,  how- 
ever, quite  fu.gitive.  We  then  tried  the  in- 
fundibular extract  of  Burroughs  Wellcome  & 
Co.  (20  per  cent.).  It  had  a  much  more 
prolonged  action  than  pituitrin,  even  when  we 
gave  the  latter  in  ounce  doses  subcutaneously. 
But  neither  pituitrin  nor  infundibular  extract 
had  the  continued  power  that  the  whole  gland 
exerts.  We  used  all  these  preparations  sub- 
cutaneously. As  the  boiled  filtered  infusion 
of  the  whole  gland  can  not  be  readily  used  we 
would  recommend  as  the  next  best  preparation 
the  20  per  cent,  infundibular  extract  of  Burroughs 

1  Ott  and  Scott,  New  York  Medical  Journal,  Dec.  10.  1908. 

2  Wiener   Klinische   Wochenschrift,    July    8,    1909,    No.    27,    p. 
983. 


92 

Wellcome  &  Co.  by  intramuscular  injection, 
in  doses  of  i  cc.  three  times  a  day.  It  should 
not  be  used  subcutaneously,  as  it  might  cause 
some  necrosis  of  the  skin  by  the  vaso-constriction. 
As  infundibular  extract  is  not  very  poisonous,  it 
can  be  used  oftener  than  three  times  a  day  if 
the  conditions  necessitate  it. 


THIRD  LECTURE— THE  CORRELATION  OF 

THE  ACTION  OF  GLANDS  WITH  AN 

INTERNAL  SECRETION/ 

Gentlemen:  The  functional  relations  between 
the  different  internal  secretions  may  be  syner- 
gistic, supplemental  and  antagonistic.  The  ac- 
tive substances  of  the  glands  are  necessary  to 
the  normal  action  of  the  nervous  system,  the 
circulation,  metabolism  and  the  growth  of  the 
tissues.  Glands  with  an  internal  secretion  are 
connected  with  the  circulatory  and  lymphatic 
system,  for  the  reception  of  materials  from  the 
blood  and  lymph  and  the  ejection  of  their  secre- 
tions into  them.  The  removal  of  one  of  these 
secretions  injures  the  whole  organism  and  espe- 
cially the  bones  and  nervous  system,  when  the 
full  growth  of  the  body  has  not  been  accomplished. 
It  is  not  easy  to  definitely  state  the  effect  of 
the  removal  of  a  certain  gland  with  an  internal 
secretion,  because  it  stands  in  a  many-sided 
relation  to  the  other  glands  with  a  similar  secre- 
tion; you  have  a  pluriglandular  action.  The 
absence  of  the  thyroid  causes  idiocy ;  of  parathy- 
roid, tetany;  of  thymus,  apathy;  of  ovary  and 
'  testis,  a  ^change  in  the  whole  psychical  condition. 
In  anencephaly  and  hemicephaly  the  adrenals 
are  small  or  absent.  In  the  human  fetus 
or  the  new-bom  they  are  normally  of  enormous 
size.     In    this    defective    development    of    the 

1  Lecture    delivered    in    the    Course    on    Physiology,  Medico - 
Chirurgical  College,  1909-1910. 


94 

brain  it  is  not  the  medulla  but  the  cortex  of  the 
adrenal  which  is  wanting.  There  is  a  remarkable 
relation  between  the  growth  of  the  brain  and  the 
adrenals.  I  might  state  that  it  will  be  necessary 
to  repeat  many  facts  noted  in  the  preceding 
lectures.  I  \vill  first  speak  of  the  action  of 
glandular  extracts  upon  the  nervous  system 
and  will  explain  to  you  what  chromaffine  sub- 
stance is. 

Chromaffine  tissue  is  a  tissue  which  stains 
readily  with  chromic  acid  or  its  salts.  This 
tissue  is  found  mainly  in  the  medulla  of  the 
adrenal,  in  some  cells  of  the  sympathetic  ganglia, 
in  the  cells  of  the  carotid  gland,  and  in  the  lower 
animals  a  collection  of  cells  at  the  point  of 
division  of  the  abdominal  aorta.  Such  collections 
of  cells  containing  chromaffine  tissue  have  been 
called,   by   Kohn,   paraganglien. 

Swale  Vincent^  found  that  an  extract  of  the 
abdominal  chromophile  body  of  the  dog  had 
precisely  the  same  powerful  effect  upon  blood 
pressure  as  an  extract  from  the  medulla  of  the 
adrenal.  He  stated  that  there  seemed  no  reason 
why  the  hypothesis  that  all  the  chromophile 
cells  had  an  internal  secretion  might  not  be 
admitted  though  .this  process  was  more  com- 
pletely elaborated  in  the  larger  chromophile 
bodies  and  in  the  adrenal  medulla. 

Langley  divided  the  sympathetic  nervous 
system.  The  true  sympathetic  arises  from  the 
dorso-lumbar    cord    and    is    distributed    to    all 

^British  Medical  Jovrnal,  1910,  p.   1151. 


95 

parts  of  the  body.  The  parasympathetic  arises 
from  the  mid-brain,  bulb  and  sacral  part  of 
the  cord,  and  its  chief  nerves  are  the  oculomotor, 
chorda  tympani,   vagus  and  nervus  erigens. 

Adrenalin  only  stimulates  the  terminals  of 
the  sympathetic  nerv'ous  system;  it  does  not 
affect  the  parasympathetic.  Adrenalin  acts  upon 
a  "receptive  substance"  interposed  between  the 
terminals  and  muscle  tissue,  according  to  Langley. 
Infundibulin  acts  upon  the  sympathetic  and 
also  upon  the  parasympathetic,  as,  for  example, 
in  the  increase  of  the  excitability  of  the  nerves 
going  to  the  uterus  and  bladder.  Thyreoidin, 
active  principle  of  thyroid,  also  acts  upon  the 
sympathetic  nervous  system  and  upon  the 
vagus. 

About  one  millionth  of  a  gram  of  adrenalin 
elevates  blood  pressure. 

In  the  case  of  the  adrenalin  we  have  a  chemical 
messenger,  a  hormone,  for  the  sympathetic. 
The  adrenal  cortex  contains  choline.  Klose  and 
Vogt  from  experiments  upon  54  dogs  where  the 
thymus  had  been  extirpated  noted  a  slight 
alteration  in  the  psychical  condition,  apathy, 
and  after  4  to  14  months  the  animal  had  a 
"cachexia  thymopriva,"  "idiotia  thymica,"  or 
idiocy. 

Removal  of  parathyroids  decreases  the  gal- 
vanic excitability  of  the  nerves.  Falta  remarks 
about  the  attempt  to  explain  tetany  after 
parathyroidectomy  by  a  deficiency  of  calcium 
that  it  would  be  very  wonderful  when  so  com- 


96 

plicated  an  affair  could  have  an  explanation  so 
simple.  Removal  of  thyroid  increases  the  galvanic 
excitability  of  nerx'es. 

Action  on  the  Blood. — The  blood  is  the  receptacle 
of  all  the  internal  secretions,  a  vehicle  for  all  the 
hormones.  The  thyroid  stimulates  the  for- 
mation of  erythrocytes  and  mono-nuclear  leuco- 
cytes. Thyreoidin  causes  a  disappearance  of 
the  eosinophile  cells  (Falta). 

The  ovary  increases  the  number  of  red  cor- 
puscles,   but   not   their   content   of   hemoglobin. 

The  liver  and  spleen  regulate  the  richness  of 
hemoglobin.  The  insufficiency  of  the  thyroid 
secretion  diminishes  the  number  of  the  red 
corpuscles,  the  amount  of  hemoglobin  and 
often  produces  an  excess  of  leucocytes. 

Adrenals  on  the  Blood. — The  majority  of  cases 
of  Addison's  disease  have  a  deficiency  of  cor- 
puscles. Adrenalin  or  adrenal  extract  excites 
the  formation  of  all  varieties  of  leucocytes  and 
diminishes  the  red  corpuscles.  Adrenalin  pro- 
duces a  leucocytosis,  especially  of  the  poly- 
nuclear  neutrophiles  and  greatly  diminishes 
the  eosinophiles  (Falta). 

Of  all  the  internal  secretions  the  adrenal  is  the 
only  one  which  is  able  in  certain  conditions  to 
decrease  the  red  corpuscles  in  a  constant  and 
progressive  manner.  As  a  rule  it  may  be  stated 
that  nearly  all  the  internal  secretions  favor  the 
formation  of  blood.  The  hormones  of  the 
internal  secretions    are  a  primary  agent  in  the 


97 
regulating    mecliamsm    of    the   manufacture    of 
blood.  1 

Parathyroids. 

Viscosity. — ^The  researches  of  Fano  and  Rossi 
have  shown  that  removal  of  the  parathyroid 
in  the  dog  does  not  have  any  influence  upon 
the  viscosity  of  the  blood.  Removal  of  the 
parathyroid  causes  a  disappearance  of  the 
eosinophile  cells. 

Blood  Coagulation. — Salvioli  believes  orchitic 
extract    retards   the    coagulation   of   the   blood. 

Prostatic  extract  according  to  Zapelli  and 
Matozzi-Scafa  in  the  dog  retards  coagulation. 
Prostatic  extract  is  very  toxic.  They  state  that 
it  has  a  paralyzing  action  upon  the  cardiac 
apparatus  and  the  center  of  respiration,  which 
I  can  confirm. 

Infundibulin  has  no  effect  upon  the  blood. 
However,  W,  Zyembicki,-  in  tumors  of  the  hy- 
pophysis,  nearly    always    found   eosinophilia. 

Removal  of  pancreas  causes  a  disappearance 
of  eosinophile  cells. 

Action  on  the  Circulation  and  Diuresis. — In 
considering  the  effect  of  some  of  the  animal 
extracts  on  the  circulation,  it  must  be  remembered 
that  T.  Klinoshita  in  Von  Fiirth's  laboratory 
has  found  o.oi  to  0.03  per  cent,  of  cholin  in  the 
pancreas,  spleen,  Hver,  kidney,  duodenum,  muscle 
and  the  lung  of  the  cow.^ 

Roger  has  found  a  h3rpotensive  substance  in 

1  Secretions  Internes,  par  Maurice  Perrin,  Paris,   1910. 

2  Wiener  Klinische  Wochenschrift,  1910,  p.  719. 
^Pfluger's  Archiv,  Band  132,  p.  631,  1910. 


98 

the  adrenals  like  that  in  thyroid  and  hypophysis.' 

Adrenalin  and  infundibulin  both  increase 
blood  pressure;  the  adrenalin  does  it  rapidly 
and  it  lasts  only  a  short  time;  infundibulin  does 
it  slowly,  but  it  lasts  for  some  time.  Adrenalin 
slows  the  heart  to  a  marked  degree,  while 
infundibulin  retards  it  only  a  little.  After 
section  of  the  vagi  the  heart  is  accelerated  by 
adrenalin.  Adrenalin  stimulates  the  cardio- 
inhibitor}^  centre  in  the  medulla  oblongata, 
infundibulin  slows  the  heart  even  after  section 
of  vagi  or  previous  atropinization  which  paralyzes 
the  vagus,  hence  the  cause  of  the  slowing  is 
seated  in  the  heart  itself.  Adrenalin  dilates 
the  coronary  arteries,  infundibulin  narrows  them. 
Adrenalin  contracts  the. renal  arteries,  infundib- 
ulin dilates  them.  Adrenalin  increases  the 
force  of  the  heart  muscle. 

Thyreoidin,  the  active  principle  of  the  thyroid, 
accelerates  the  heart  beat  and  the  blood  pressure 
is  not  elevated. 

Jeandelize  and  Parisot  found  in  a  rabbit  who 
was  thyroidectomized  in  his  youth  that  after  a 
certain  time  there  was  arterial  hypotension. 
The  serum  of  the  animal  also  lowered  arterial 
tension.  In  thyroid  insufficiency  of  man  there 
was  a  lower  blood  pressure. - 

lodothy rin  ( i  grain)  increased  the  flow  of  urine 
to  a  small  extent.  It  also  increased  the  volume 
of  the  kidney,  although  at  the  time  the  general 

1  Compi.  rend.  Soc.  de  Biol..  1910.  Tome  69,  p.  160. 

2  Journal    de    Physiologie    et    de    la    Paihologie    generate,    1910, 
p.  339. 


99 

blood  pressure  was  decreasing  the  heart-beat 
remained  the  same.  The  first  injection  of 
iodothyrin  in  the  cat  elevated  for  the  moment 
arterial  tension,  but  it  soon  fell.  The  heart- 
beat was  increased. 

Coronedi^  confirms  my  results.  He  found  the 
thyro-parathyroid  secretion  kept  the  secretory- 
activity  of  the  kidneys,  adequate  to  the  needs 
of  the  organism  in  dogs  thyroidectomized. 
After  thyroidectomy  the  kidney  of  the  dog  has 
a  functional  insufficiency. 

Spinal  cord  (i/8  grain)  had  no  effect  on  flow 
of  urine;  did  not  alter  rate  of  pulse;  increased 
blood  pressure. 

Prostate  had  no  effect  on  urinary  flow;  did  not 
alter  pulse  rate;  increased  blood  pressure. 

Ovary  reduced  flow  of  urine;  did  not  alter 
pulse  rate,  but  reduced  arterial  tension. 

Spleen  (3^  grain)  reduced  urinary  flow;  did 
not  alter  pulse  rate;  lowered  arterial  tension. 

Testicular  extract  (i/8)  grain)  did  not  affect 
flow  of  urine  or  pulse;  increased  arterial  tension. 

Bielow^  found  that  the  secretion  of  the  corpus 
luteum  lowered  blood  pressure  and  slowed  the 
heart.  He  also  calls  the  corpus  luteum  the 
"glandula  lutea  ovarii." 

Mammary  gland  (1/50  grain)  produces  a 
slight  increase  of  diuresis.  The  volume  of  the 
kidney  increased  at  the  time  the  blood  pressure 
was  falling,  while  the  heart-beat  was  somewhat 

1  Journal  de  Physiologie  et  de  Pathologic.  1910,  p.  599. 
^  Muenchener  Medizinische  Wochenschrift,  1910,  p.  1707. 


lOO 

increased.  In  the  cat  the  mammary  gland 
extract  increases  the  heart-beat  and  temporarily 
increases  the  general  arterial  tension,  after  which 
it  falls  considerably. 

The  parathyroid  powdered  extract  (i/io  to 
1/5  grain)  at  first  decreases  the  volume  of  the 
kidney  and  then  gradually  increases  it.  The 
increase  of  the  kidney  volume  is  often  so  great 
that  the  registering  pen  cannot  record  it.  The 
primar}'^  decrease  of  kidney  volume  is  due  to  a 
temporary  slowing  of  the  heart.  The  subsequent 
increase  of  volume  in  the  kidney  is  not  due  to 
any  change  in  the  rate  of  heart-beat,  and  the 
general  blood  pressure  at  the  time  fell  slightly. 
As  a  diuretic,  the  parathyroids  were  the  most 
powerful  of  all  the  gland  extracts.  With  the 
nucleoproteid  prepared  according  to  Beebe's 
method  by  Dr.  W.  N.  Berkeley  the  increase  in 
the  amount  of  urine  was  ten  times  that  of  normal. 
We  found  the  parathyroids  in  a  case  of  inter- 
stitial nephritis  increased  the  quantity  of  urine 
a  half  pint  a  day. 

Thymus  slightly  increased  the  flow  of  urine. 
It  also  augmented  the  volume  of  the  kidney, 
although  the  pulse  rate  remained  unaltered  and 
the  arterial  tension  was  falling. 

Lucien  and  Parisot  found  the  thymus  extracts 
lowered  blood  pressure.  They  think  this  is  due 
to  the  lymphatic  tissue  in  the  gland  and  not  the 
gland  itself  or  the  corpuscles  of  Hassal.^ 

The-  pancreas    increased    the    flow    of    urine. 

>  Zentralblaii  f.  Physiologi-e,  Band  24,  p.  2401. 


lOI 

The  volume  of  the  kidney  was  slightly  increased, 
while  the  general  blood  pressure  was  decreasing, 
and  the  rate  of  heart-beat  considerably  increased. 

After  injection  by  jugular  of  pancreas  the  urine 
contained  1/4  per  cent,  of  sugar,  as  shown  by 
the  fermentation  and  Fehling's  test. 

Schaefer,  Houghton  and  Merril  have  shown 
that  the  pituitary  extract  (infundibular  part) 
increased  the  flow  of  urine.  The  volume  of 
the  kidney  was  greatly  augmented,  so  much  so 
that  the-  lever  could  not  register  at  times.  In- 
fundibulin  per  jugular  causes  glucose  to  appear 
in  the  urine. 

The  renal  cortex  increased  the  flow  of  urine. 
The  volume  of  the  kidneys  in  doses  of  1/50 
to   1/25  of  a  grain  did  not  change. 

Adrenalin  decreased  momentarily  the  volume 
of  the  kidney,  while  the  blood  pressure  rose  and 
the  heart  was  slowed.  Afterwards  the  kidney 
volume  was  greatly  increased. 

All  these  agents,  the  renal  cortex,  pituitary 
extract,  pancreas,  parathyroid,  mammary  gland, 
thymus,  iodothyrin  and  adrenalin,  are  diuretics. 
Gouin  and  Andouard  found  thymus  in  large 
doses  produced  diuresis  in  the  calf.  The  above 
agents,  except  adrenalin,  do  not  markedly  in- 
crease general  arterial  tension,  except  for  a 
moment,  and  then  lower  it.  It  is  inferred  that 
the  very  short  rise  of  blood  pressure  does  not 
produce  the  diuresis,  which  continues  for  a 
considerable  time  afterwards. 

As  the  changes  of  arterial  tension  do  not  play 


I02 

any  large  part  in  the  diuresis,  it  must  be  referred 
to  an  action  on  the  renal  epithelium  itself. 

Action  upon  Intestinal  Peristalsis. — Adrenalin 
arrests  it  temporarily  (Fig.  14),  infundibulin 
accelerates  it.  lodothyrin  increases  the  fre- 
quency and  extent  of  contraction.  Parathyroid, 
mammary  gland,  spleen  (Fig.  15),  pancreas, 
prostate,  thymus,  parotid,  brain  and  spermine 
(Poehl)  increased  the  contractions.^ 

Action  upon  Movements  of  Bladder. — Adrenalin 
stops  them  temporarily,  infundibulin  increases 
them.  If  the  nervi  pelvici  in  the  cat,  which 
contain  motor  and  (according  to  Langley)  also 
inhibitory  fibers,  are  cut  then  infundibulin  has 
a  very  weak  action.  This  shows  it  mainly 
causes  contractions  of  bladder  by  stimulating 
the  vesico-spinal  center.  As  Von  Frankl-Hoch- 
wart  and  Frohlich  have  pointed  out  it  increases 
the  irritability  of  the  nervi  pelvici.  I  can 
confirm  this. 

Thyroid  extract  produced  strong  vesical  con- 
tractions. 

Parathyroid  increased  the  contractions  of  the 
bladder. 

Pancreas  increased  the  vesical  contractions 
normally  and  after  section  of  the  nervd  pelvici. 

Normally  thymus  increased  the  extent  of 
the  contractions  of  the  bladder. 

Ovary  normally  increased  the  extent  of  con- 
tractions of  the  bladder. 

'  Ott  and  Scott,   Unpublished  experiments,  1910. 


■;mmmmmmmmmwmm!>mwmmitimtmm^i 


T.mmmmmtttttmm' 


spleen  extract  upon 


ncreas  extract  upo 


I03 

Parotid  considerably  increased  the  frequency 
of  the  contractions  of  the  bladder. 

Brain  extract  increased  the  frequency  of  the 
vesical  contractions.^ 

Action  upon  the  Uterus. — Adrenalin  in  unim- 
pregnated  uterus  of  the  cat  relaxes  the  uterus; 
in  a  pregnant  uterus  it  causes  contraction.  Here 
the  hypogastric  nerv^e  contains  both  augmentor 
and  inhibitory  fibers  going  to  the  uterus.  In- 
fundibulin  stimulates  the  cat's  uterus  to  a  marked 
contraction^  so  does  iodothyrin,  parathyroid, 
mammary  gland,  spleen  (Fig.  i6),  pancreas  and 
prostate  (Fig.  17).  Thymus  and  spermine 
had  some  effect.  Ovary  had  a  very  slight 
action  on  unimpregnated  uterus. 

Action  upon  Pupil. — Adrenalin  dilates  the 
pupil  in  rabbit  with  superior  cervical  ganglion 
excised  and  in  large  doses  the  normal  pupil. 
Pituitary  extract  and  pituitrin  dilates-  the  ex- 
cised pupil  of  the  frog,  and  the  pupil  in  the 
rabbit  on  the  side  where  the  superior  cervical 
ganglion  is  excised. 

Iodothyrin  dilates  the  pupil  on  the  side  where 
the  superior  cervical  ganglion  was  excised;  no 
effect  upon  normal  pupil.  The  dilation  was 
preceded  by  a  slight  contraction. 

Parathyroid  nucleoproteid  on  the  normal  eye 
dilated  the  pupil,  on  the  side  with  excised  superior 
cervical  ganglion;  it  at  first  contracted  and  then 
dilated  it.     The  mammary  gland  had  no  effect. 

Thymus  had  no  effect  upon  the  pupil. 

1  Ott  and  Scott,   Unpublished  experiments,  1910. 

2  ott  and  Scott,  American  Journal  of  Obstetrics,  1910,  p.  766. 


I04 

t:;  Parotid  and  testicular  extract  contracted  the 
pupil  upon  both  sides,  the  normal  one  and  the 
one  with  excised  superior  cervical  ganglion. 

The  ovary  had  no  effect. 

Action  on  Temperature. — Narbut,  like  Vassale 
and  Sacchi,  in  Von  Bechterew's  laboratory,  found 
after  removal  of  the  hypophysis  a  lowering  of 
the  temperature  on  the  day  of  operation  and  a 
marked  sinking  of  it  before  death. 

Gushing  has  shown  that  the  removal  of  the 
anterior  part  of  the  pituitary  lowers  temperature 
to  a  great  degree  and  injection  of  the  pars  an- 
terior again  elevates  this  low  temperature. 

Adrenalin  increases  temperature. 

Infundibulin  has  a  similar  effect. 

Glandular  Glycosurias. — In  1889,  Me  ring  and 
Minkowski  made  a  total  extirpation  of  the 
pancreas  and  observed  sugar  in  the  urine. 

Forsbach^  has  made  some  experiments,  in 
which  two  dogs  of  the  same  kind  and  same 
brood  had  the  skin,  muscle  and  peritoneum  of 
each  united  together  by  ligatures.  Here  an 
exchange  of  blood  takes  place  by  the  newly 
formed  blood  vessels  and  an  exchange  of  lymph 
through  the  communication  of  peritoneal  cav- 
ities. He  showed  that  many  things,  as  iodine, 
sugar,  strychnine,  and  so  on,  went  from  one 
animal  to  the  other.  If  now  in  the  living. dogs 
the  pancreas  is  extirpated  in  one,  then  the  usual 
glycosuria  did  not  ensue  to  the  usual  extent, 
and  in  many  cases  was  very  little.     If,  however, 

'  Deutsches  Medizinische  Wochenschrift.  1908. 


I05 

the  depancreated  dog  was  separated  from  the 
normal  dog,  then  glycosuria  took  place  to  the 
usual  extent  in  the  animal  without  the  pancreas. 

Minkowski  and  Hedon  found  in  dogs  that  if 
a  transplant  of  a  piece  of  the  pancreas,  the 
"processus  uncinatus,"  is  made  under  the  skin 
of  the  abdomen  and  simultaneously  or  later  the 
remainder  of  the  pancreas  and  its  duct  be  ex- 
tirpated, the  appearance  of  sugar  in  the  urine 
was  usually  prevented,  but  ensued  after  removal 
of  the  piece  of  pancreas  in  the  subcutaneous 
tissue.  Pfiiiger  ascribes  the  appearance  of  gly- 
cosuria after  removal  of  the  pancreas  to  injury 
of  nerves  in  the  duodenum.  His  view  has  been 
contradicted  by  many  observers. 

It  has  been  inferred  that  in  the  cells  of  islets 
of  Langerhans  we  have  the  internal  secretion  of 
the  pancreas.  Severe  diabetes  can  occur  without 
changes  in  the  pancreas. 

Opie  studied  very  carefully  the  pancreas  of 
five  diabetics.  In  three  he  observed  marked 
total  hyaline  degeneration  of  the  islets.  In 
two  others  the  degeneration  was  less  marked. 
Similar  degenerations  were  not  found  by  him 
in  the  pancreas  of  non-diabetics.  In  the  di- 
abetic cases  the  parenchyma  of  the  acinus  was 
more  or  less  altered.  Ugo  Lombroso,^  from  a 
review  of  the  literature  of  pathological  and 
anatomical  facts,  states  that  the  internal  function 
of  the  pancreas  can  not  be  provided  by  only  one 
of  the  tissues  of  the  gland,  be  it  acini  or  islets. 

^  Ergebenisse  der  Physiologie,  1910,  p.  47. 


io6 


Lombroso,'  from  an  analysis  of  experimental 
work  upon  animals,  concludes  that  both  epi- 
thelial tissue  of  pancreas,  the  acini  as  well  as 
the  islets,  take  part  in  the  internal  secretion. 

Cohnheim  has  shown  that  if  the  pancreas, 
which  contains  a  body  not  a  ferment,  and  called 
by  him  the  activator,  is  mixed  with  muscle 
extract  in  certain  proportions,  that  the  mixture 
is  a  marked  glycolytic  agent.  His  theory  has 
been  contradicted. 

Adrenalin  and  infundibulin  produce  glycosuria, 
the  former  after  section  of  the  splanchnics; 
infundibulin  has  no  effect  after  splanchnicotomy. 
After  extirpation  of  adrenals,  diabetic  puncture 
fails  to  cause  sugar  in  urine. 

Parathyroid  and  pancreas  in  large  doses 
subcutaneously  in  rabbits  produce  a  slight 
glycosuria,  i/8  per  cent.  Extirpation  of 
thyroid  reduces  the  glycosuric  action  of  in- 
fundibulin, pancreas  and  parathyroid.  In  some 
cases  of  dogs  and  cats  sugar  appears  after  ex- 
tirpation of  the  thyroid  alone. 

It  seems  that  the  absence  as  well  as  the  excess 
of  the  internal  secretion  of  the  pancreas  conduces 
to  glycosuria. 

In  thyroidectomized  dogs  Falta  states  that 
adrenalin  produces  no  glycosuria.  Underhill, 
however,  finds  that  if  the  dose  is  large  enough 
sugar  appears  in  the  urine. 

The  present  theory  of  diabetes  is  that  a  gly- 
co-secretory  center  exists  in  the  medulla  oblongata, 

1  Ergebenisse  der  Physiologic,  1910,  p.  89. 


loy 

from  which  fibers  run  down  the  cervdco-dorsal 
cord  to  the  solar  plexus  and  then  in  the  trunk 
of  the  splanchnics  to  the  liver  cell.  Falta 
states  that  high  section  of  the  spinal  cord,  or 
the  withdrawal  of  the  adrenals  by  section  of 
its  nervous  connection  with  the  diabetic  center, 
leads  to  a  very  marked  reduction  of  the  amount 
of  sugar  in  the  blood,  like  when  you  extirpate 
the  adrenals  themselves.  Fom  the  analogous 
effects  of  diabetic  puncture  compared  with 
adrenalin  injections,  it  is  inferred  that  the 
sympathetic  fibers  actuate  the  formation  of 
sugar  in  the  liver  lia  the  adrenals  (Schur  and 
Wiesel).  Normally  diabetic  puncture  increases 
the  amount  of  adrenalin  in  the  blood. 

Falta  states  that  after  bilateral  section  of 
the  vagi  the  content  of  sugar  in  the  blood  is 
elevated.  There  was  also  a  well  marked  increase 
and  hypertrophy  of  the  cells  of  Langerhans  in 
3  dogs  who  had  their  thyroid  removed  six  months 
previously.  These  facts  lead  Falta  to  think 
that  by  the  vagus  and  pancreas  we  have  an 
inhibitor}^  action,  on  the  production  of  sugar 
and  an  increase  of  sugar  by  the  sympathetic 
via  the  adrenals  on  the  liver  cell.  By  this 
checking  action  the  level  of  the  content  of  sugar 
in  the  blood  is  kept  constant. 

As  Boruttau  puts  it,  the  adrenals  produce 
a  hormone  which  sets  in  motion  glycogeny  in 
the  liver  while  the  pancreas  furnishes  another 
hormone  by  its  internal  secretion  which  an- 
tagonizes   the    sugar    driving    function    of    the 


io8 

adrenals.  Hence  the  diabetes  after  pancreatic 
extirpation  is  a  negative  pancreatic  diabetes 
and  a  positive  adrenal  diabetes. 

Irritation  of  the  sympathetic  in  the  neighbor- 
hood of  the  adrenals  increases  the  amount  of 
adrenaUn  secreted  Adrenalin  solution  i  :  1000,000 
flowing  into  a  vein  (4.1  cubic  centimeters  per 
minute)  produces  adrenalin  glycosuria  according 
to  Straub. 

Phmglandidar  Action. — Just  as  glands  with 
an  external  secretion  concur  in  taking  up  the 
work  not  accomplished  by  the  others,  and  unite 
in  the  perfection  of  the  products  to  be  brought 
forth,  in  a  similar  way  the  glands  with  an  internal 
secretion  concur  in  the  metabolites  to  be  pro- 
duced, a  sort  of  physiological  balance  is  main- 
tained between  the  activities  of  the  different 
glands  in  the  wilderness  of  metabolism. 

Klose  and  Vogt,  from  experiments  upon  54 
dogs  in  whom  they  extirpated  the  thymus, 
had  the  following  results:  in  the  first  2  to  3 
months,  their  weight  increased  like  in  the  control 
animals.  There  was  slight  alteration  in  their 
psychical  condition,  apathy,  increased  appetite, 
they  were  fat,  the  stage  of  adiposity.  Then 
the  weight  sank  more  or  less  rapidly  and  this 
phase  lasted  4  to  14  months.  The  animals 
were  idiotic,  "cachexia  thymipriva"  (iodiotia 
thymica) ;  they  had  spontaneous  fractures.  Fin- 
ally the  animals  died  in  a  state  of  thymic  coma 
lasting  5  to  8  days.  Rachitis,  osteomalacia  and 
osteoporosis  were  present  in  the  same  animal. 


I09 

The  common  cause  was  a  great  want  of  calcium 
in  the  thymected  organism.  The  cause  of  the 
deficiency  of  calcium  and  the  idiocy  is  an  acidosis. 
Klose  holds  that  the  thymus  is  the  chief  organ 
for  the  synthesis  of  nuclein. 

The  removal  of  the  thymus  permits  the  lower 
building  stones  of  the  organism,  perhaps  a  great 
excess  of  the  incombustible  phosphoric  acid  to 
circulate  in  the  blood.  The  acid  dissolves  the 
calcium  salts,  or  holds  them  in  solution.  Arti- 
ficially produced  fractures  do  not  unite  with 
callus  but  only  with  connective  tissue.  The 
chief  organ  which  substitutes  for  the  thymus 
is  the  spleen.  It  acts  after  the  phase  of  in- 
volution of  the  thymus.^ 

Worms  and  Pigache^  found  in  thyroidectomized 
dogs  and  rabbits  a  disappearance  of  the  thymus 
which  was  replaced  by  connective  tissue. 

Renon  and  Delille*  have  found  that  injections 
of  the  extract  of  the  hypophysis  cause  a  hyper- 
function  and  very  often  hypertrophy  of  the 
adrenals.  Inversely  the  hypophysis  of  animals 
treated  by  the  adrenals  have  been  found  con- 
gested and  in  hyperactivity.  Parhon,  Hallion 
and  Alquier,  Renon  and  Delille  are  in  concord 
about  this  result. 

New  researches  by  Renon  and  Delille  tend  to 
demon  irate  that  it  is  only  the  extract  of  the 
posterior  lobe  of  the  hypophysis  which  causes 
a    hypertrophy    of    the    adrenals.     The    extract 

1  Muenchener  Medizinische  Wochenschrift,  1910,  p.  874. 

2  Compi.  rend.  Soc.  de  Biol.,  LXVIII,  32,  p.  500. 

3  C.  R.  Soc.  de  Biol.,  June  13,  1908, 


no 

of  the  anterior  lobe  is  without  eflfect,  but  pro- 
vokes a  hyperfunction  of  the  thyroid,  while 
the  extract  of  the  posterior  lobe  has  an  opposite 
action  upon  the  thyroid. 

Tandler^  holds  that  in  the  sexual  glands  we 
have  (i)  a  generative  part,  and  (2)  a  part  devoted 
to  an  internal  secretion.  If  you  apply  the  X-rays 
to  the  testes,  then  the  generative  part  is  destroyed, 
but  the  internal  secretion  remains.  The  same 
result  can  be  obtained  to  a  certain  extent  by 
ligature  of  the  vas  deferens.  I  shall  give  you 
an  abstract  of  Tandler's  lecture  upon  this  subject 
before  the  Royal  Medical  Society  of  Vienna. 

Tandler,  from  an  examination  of  the  testes 
in  about  20  cases  of  cryptorchids,  found  in  all 
an  absence  of  spermatogenesis,  but  regularly 
normal  developed  Leydig  cells.  The  bilateral 
cryptorchid  has  the  normal  primary  and  second- 
ary sexual  characters,  except  he  has  azoospermia, 
otherwise  he  is  a  normal  individual. 

Nielsen  examined  the  testes  in  20  cryptorchids 
in  the  horse,  and  at  no  time  saw  spermatogenesis. 
These  facts  show  the  worth  of  the  interstitial 
cells. 

By  these  facts  he  has  arrived  at  the  conclusion 
that  the  interstitial  cells  are  the  parts  of  the 
testes  concerned  in  the  changes  in  the  external 
form  of  the  body.  The  interstitial  cells  in  the 
ovary"  are  those  in  the  stroma  of  this  body. 
The  corpus  luteum  inhibits  the  internal 
secretion  of  the  ovary.     In  the  castrated  female 

'  Wiener,  Klinische  Wochenschrift,   1910,  p.  459. 


Ill 

and  in  the  pregnant  one  the  hypophysis  is 
enlarged,  hence  there  is  a  relation  between  the 
ovary  and  the  hypophysis.  In  the  cow  there 
is  not  seldom  a  hypertrophy  and  persistence 
of  the  corpus  luteum  reaching  the  size  of  a  nut. 
In  this  condition  the  state  of  "heat"  does  not 
come  on  every  2 1  days.  If,  however,  the  corpus 
luteum  is  extirpated,  then  typical  heat  comes 
on  in  a  few  days.  In  woman,  there  is  a  per- 
sistence of  the  corpus  luteum  of  pregnancy. 
At  the  same  time,  as  a  rule,  ovulation  is  absent 
in  the  cyclical  activity  of  the  ovary.  The  same 
state  of  affairs  persists  after  delivery,  that  is, 
the  corpus  luteum  may  be  the  cause  of  delayed 
menstruation  during  lactation.  The  interstitial 
cells  of  the  ovary  are  concerned  with  the  internal 
secretion  of  the  ovary.  The  action  of  the  inter- 
stitial cells  of  these  sexual  glands  upon  the 
form  of  the  body  starts  in  embryonic  life.  The 
dimensions  of  the  body  and  the  changes  in  the 
skeleton  are  conditioned  upon  the  internal 
secretion  of  the  sexual  glands.  We  know  that 
castration  and  hypoplasia  of  the  sexual  glands 
leaves  the  epiphyses  unjoined.  During  preg- 
nancy the  persistence  of  the  corpus  luteum  is 
inhibitory  of  an  internal  secretion  of  the  ovary. 
Loeb^  holds  that  at  a  certain  period  of  "heat" 
a  few  ovarian  follicles  rupture  and  become 
transformed  into  corpora  lutea.  In  the  early 
stages  of  their  life  the  corpora  lutea  constitute 
one  of  the  factors,  initiating  growth  processes  in  the 

1  Journal  Am.  Med.  Association,  1910,  July  9,  p.  166. 


112 

uterine  mucosa  by  means  of  an  internal  secretion. 
If  pregnancy  takes  place  the  ovum  adds  a  me- 
chanical stimulus  to  the  sensitizing  action  of 
the  corpus  luteum  and  a  maternal  placenta  is 
produced.  A  foreign  body  placed  in  the  uterus 
can  do  the  same  as  the  ovum.  In  this  period 
the  corpus  luteum  exerts  a  new  function,  it 
prevents  the  rupture  of  new  follicles  and 
prolongs  artificially  the  period  of  the  sexual 
cycle.  Starling  has  shown  that  the  dried  embryo 
contains  a  hormone  which  by  the  blood  stimulates 
the  growth  of  the  mammary  gland. 

The  placenta  according  to  Von  Basch  causes 
the  growth  of  the  mammary  gland  even  when 
the  nerves  of  the  mamma  are  cut  or  even  when 
the  gland  is  transplanted.  The  mammary  gland 
of  the  fetus  often  secretes  milk,  from  the  same 
cause  in  the  blood  of  the  mother. 

Rapid  development  of  puberty  goes  with 
early  juncture  of  the  epiphysis  to  the  diaphysis 
and  necessarily  short  bones. 

Hypoplasia  of  the  sexual  glands,  or  late  puberty 
of  the  individual,  produces  long  bones.  In 
mankind  the  earlier  puberty  of  the  femal  com- 
pared with  the  male  makes  her  bones  shorter. 
Hence,  early  puberty  in  hot  climates  produces 
individuals  short  in  stature,  while  late  puberty 
of  cold  climates  produces  tall  individuals. 

The  influence  of  the  sexual  glands  is  seen  in 
the  subcutaneous  fat  in  castrates,  at  the  meno- 
pause and  in  old  age.  The  hypophysis  is  a 
regulator  of  the  growth  of  the  bones,  especially 


113 

in  the  promotion  of  their  growth.  The  castrate 
becomes  tall  from  the  greater  action  of  the 
anterior  part  of  the  hypophysis. 

Nussbaum^  found  in  frogs  castration  caused  the 
secondary  sexual  characteristics  to  disappear 
if  the  operation  was  done  in  their  youth.  The 
pads  on  the  thumbs  disappear  in  the  male. 
If  you  inject  testicular  material  from  the  same 
species  then  they  appear.  Feeble  nutrition 
plays  no  part  here. 

Hypofunction  of  the  ovary  produces  changes 
in  the  hypophysis,  which  changes  the  growth 
of  the  skeleton. 

As  to  the  growth  of  fat  connected  with  the 
sexual  glands,  we  can  speak  of  a  hypophyseal  fat. 

As  to  the  relation  of  the  thyroid  to  the  sexual 
glands,  we  must  remember  the  sterility  of  the 
cretins,  the  genital  disturbances  in  Basedow's 
disease,  and  the  changes  in  the  thyroid  at  the 
time  of  menstruation,  during  pregnancy  and 
at  the  menopause. 

Walter  Edmunds  has  found  that  lo  grains 
of  thyroid  extract  administered  three  times 
a  day  to  rats  will  cause  death  in  about  twenty 
days  from  congestion  and  hemorrhage  into  the 
adrenals.^ 

Thyroid  and  Growth  of  Bones. — H.  Bircher^ 
studied  the  effect  of  thyroid  tablets  upon  the 
growth  of  bones.     He  found  the  thyroid  tablets 

1  Pfluger's  Archiv.,  1909,  Band  129.  p.  110. 

2  Personal  communication. 

3  Archiv.  Klin.  Ckir.,  Band  91.  Heft  3,  s.  554. 


114 

lead  to  a  more  rapid  calcification  of  the  epiphyses 
of  the  bone.  They  did  not  (as  expected)  lead 
to  an  increase  in  the  length  of  the  bones. 

Adrenals.— In  the  disease  of  the  chromafhne 
tissue  of  the  adrenals,  or  Addison's  disease,  we 
often  have  impotency  and  menstrual  disturbances. 
In  a  case  of  Addison's  disease,  post-mortem 
sections  of  the  testis  by  Kyrle  showed  especially 
a  want  of  spermatogenesis,  and  changes  in  the 
interstitial  cells.  In  a  case  of  h3^poplasia  of 
the  adrenals  with  an  absence  of  the  right  adrenal 
while  the  left  adrenal  was  small  and  flat  and  the 
cortex  could  hardly  be  seen,  Schlangenhaufer 
found  similar  but  much  more  developed  changes 
in  the  testis.  In  the  pseudo-hermaphrodites 
there  is  enlargement  of  the  adrenals. 

Hypertrophy  of  adrenals  is  seen  during  men- 
struation and  pregnancy.  Here  the  changes 
in  the  adrenals  are  probably  the  primary  cause 
of  changes  in  the  ovary. 

Hallion  and  Alquier  have  seen  the  prolonged 
ingestion  of  adrenals  cause  histological  changes 
in  the  thyroid  and  adrenals.  They  found  no 
lesions  in  the  kidney,  testis,  liver  or  hypophysis.^ 

Ovaries  and  Adrenals. — F.  Schenk-  holds  that 
adrenals,  ovaries  and  testicles  have  a  definite 
relation  to  each  other.  Castrated  male  or 
female  rabbits  have  a  hypertrophy  of  the  adrenals 
and  the  hypertrophy  is  chiefly  localized  in  their 
cortex. 

1  Compt.  rend.  Soc.  de  Biol.,  1910,  Tome  68,  p.  966. 

2  V.  Brunnsche  Beitrdge  zur  Klin.  Chirurg.  Bd.,  67. 


115 

Ovaries  and  Hypophysis. — E.  Mayer^  concludes 
that  the  hypophysis  enlarges  after  castration 
and  after  diseases  in  which  there  is  a  partial  or 
complete  rest  of  the  ovaries  or  testicles. 

Alquier^  finds  after  ovariotomy  less  marked 
histological  changes  in  the  hypophysis  and  thy- 
roids than  in  animals  which  have  been  castrated. 
The  changes  in  the  hypophysis  and  thyroid 
are  due  to  hyperf unction  of  these  glands.  As 
to  the  effect  of  removal  of  ovaries  upon  the 
adrenals  the  effects  are  yet  doubtful. 

Thymus. — The  thymus  and  sexual  glands  are 
complementary  glands,  thus  the  persistence  of 
the  thymus  in  castrates  and  eunochoids.  Persist- 
ence of  the  thymus  is  a  sign  of  general  want 
of  maturity  in  the  organism.  In  guinea  pigs 
and  bulls,  removal  of  thymus  causes  the  testes  to 
greatly  increase  in  size,  hence  it  is  probable 
that  the  thymus  has  an  internal  secretion  which 
controls  the  growth  of  the  testes. 

Soli  found  in  cocks  that  ablation  of  the  thymus 
retards  the  growth  of  the  testicles.  If  the 
cock  lives  until  his  period  of  copulation,  then 
the  testis  attains  its  normal  development.  He 
holds  that  the  thymus  is  in  relation  not  only 
with  the  development  of  the  skeleton,  but  with 
the  regular  and  physiological  development  of 
the  testis.^ 

Enlarged  hypophysis  inhibits  the  ovary  and 

1  Archiv.  f.  Gynekol.,  1910,  Band  90. 

2  Gaz.  d.  hopiial,  No.  59. 

3  Journal   de   Physiologie   et   de   Pathologie   generate,     1910,     p. 
599. 


ii6 


testis.  Between  the  testis  and  ovary  on  one 
side  and  the  adrenal  and  thymus  on  the  other 
there  is  an  atagonism. 

Landau/  after  removal  of  tht  adrenals,  found 
no  changes  in  the  hypophysis,  thyroid  and 
ovary.  Feodossjeff^  after  removal  of  the  ovary 
found  a  marked  hyperplasia  of  the  cell  elements 
of  the  adrenals. 

Falta  has   made   the   most   lucid   explanation 
of    pluriglandular     action.       His    theories    rest 
upon  solid  experimental  work. 
Th 


C.S. 


INHIBITION 

Fig.   18. 


Th  =  thyroid.  P  =  pancreas.  C.  S.  Chromaffine  sub- 
stance. Between  Th  and  P,  as  well  as  between  P  and  C.  S., 
there  is  a  reciprocal  inhibition;  between  Th  and  C.  S.,  a 
reciprocal  promotion  of  each  other's  functions.  The  in- 
hibition is  stronger  than  the  promotion  (Falta). 

1  Experimentelle  Nebennieren  Siudien,    1908. 
-  From  Landau's  work. 


117 

The  following  is  an  abstract  of  Falta's  paper.^ 
As  Falta  has  stated,  the  removal  of  a  gland 
with  an  internal  secretion  produces  two  results: 
(i)  the  direct  action  of  absence  of  the  internal 
secretion  of  the  gland,  and  (2)  an  indirect  action, 
by  the  disturbance  of  the  metabolism  iii  relation 
to  the  other  glands,  as,  for  instance,  between 
the  thyroid  and  pancreas  there  is  inhibition 
against  each  other,  between  the  pancreas  and 
chromaffine  tissue  a  reciprocal  inhibition,  while 
between  the  thyroid  and  chromaffine  tissue  there 
is  a  reciprocal  promotion  of  activity.  Thus, 
extirpation  of  thyroid  leads  by  removal  of  the 
inhibition  to  hyper-function  of  the  pancreas; 
the  extirpation  of  thyroid  by  the  removal  of 
its  power  of  promotion,  to  diminished  adrenal 
action.  On  the  other  hand,  increased  hyperthy- 
roidism by  increased  inhibition  leads  to  relative 
insufficiency  of  the  pancreas.  Hyperthyroidism, 
through  increase  of  the  promoting  influences, 
leads  to  increased  adrenal  action.  Extirpation 
of  the  pancreas  by  the  retnoval  of  its  internal 
secretion  directly  prevents  destruction  of  the 
sugar,  indirectly  to  absence  of  an  intense  inhibi- 
tion of  the  thyroid,  a  hyperf unction  of  the 
thyroid,  which  results  in  an  increase  of  the 
metabolism  of  the  proteids,  fats  and  inorganic 
materials.  If  the  pancreas's  intense  inhibition 
upon  the  chromaffine  tissue  is  removed,  there 
is  a  hyperfunction  of  the  chromafhne  tissue,  with 

1  Eppinger,    Falta    und    Rudinger,    Zeitschrift    fiir    Klinische 
Medizin,   1908,  pp.  1-52. 


ii8 


consecutive,  excessive,  rapid  mobilization  of 
the  carbohydrates.  The  promotion  of  the  ac- 
tivity of  the  chromafiine  tissues  directly  is  by 
the  removal  of  the  intense  inhibition  of  the 
pancreas  on  the  chromafiine  tissue,  and  indirectly 
by  the  removal  of  the  inhibition  of  the  pancreas 
on  the  thyroid,  and  thereby  to  increase  of  the 
thyroid  promoting  action  on  the  chromalKine 
tissue,  that  is,  the  activity  of  the  chromafhne 
tissue  is  greatly  increased.  In  this  way  the 
well  known  intensity  of  pancreatic  diabetes  is 
explained,  and  the  two  theories  of  diabetes,  one 
a  disturbance  in  the  destruction  of  sugar,  the 
other,  a  disturbance  in  formation  of  glycogen; 
both  may  be  right — due,  according  to  the  first 
theory,  to  removal  of  pancreas;  the  second 
theory,  to  a  hyperf unction  of  the  chromaffine 
tissue. 

Porges  has  shown  in  dogs  that  extirpation 
of  both  adrenals  causes  a  lowering  of  the  amount 
of  sugar  in  the  blood  and  only  a  small  amount  of 
glycogen  is  to  be  found  in  the  liver  and  muscle, 
although  they  were  tested  a  few  hours  after  the 
operation.^ 

We  can  produce  hyperaction  of  the  adrenals 
by  injection  of  adrenalin.  Then,  as  expected, 
we  directly  have  rapid,  excessive  mobilization 
of  the  carbohydrates,  and  indirectly  an  inhibi- 
tion of  the  pancreas  function.  By  both  ways 
we  have  glycosuria.  As  a  further  indirect  result 
by  the  promotion   of  the   thyroid,    an  increase 

^Berlin.  Klin.  Wochenschrift.  No.  25,  p.  1187. 


119 

in    the    metabolism    of    the    proteids    and   fats. 

In  extirpation  of  the  thyroid  we  have  as  a 
direct  action  the  removal  of  the  thyroid  secretion, 
and  hence  a  depression  of  the  metabolism  of 
the  albumens,  fats  and  inorganic  salts,  as  an 
indirect  action  by  the  removal  of  the  promotion 
of  the  thyroid  on  the  chromaffine  substance, 
a  slower  mobilization  of  the  carbohydrates, 
and  probably  of  the  fats.  Also  by  the  want 
of  the  thyroid  we  find  an  absence  of  the  intense 
inhibition  of  the  thyroid  on  the  pancreas;  we 
have  hyperfunction  of  pancreas,  which  explains 
why  thyroidless  dogs  do  not  have  glycosuria  by 
injections  of  adrenalin. 

In  depancreatized  dogs,  by  adrenalin  injection, 
we  have  a  secondary  hyperfunction  of  the 
chromaffine  tissue,  hence  an  increased  destruction 
of  the  proteids  and  fats,  and  the  quotient  of 
dextrose  to  nitrogen  is  raised.  Here  we  have 
the  mobilization  of  carbohydrates  by  adrenalin. 

After  removal  of  the  thyroid  and  pancreas 
we  have  complicated  relations. 

The  removal  of  the  inhibition  of  the  pancreas 
upon  the  chromaffine  tissue  is  stronger  than  the 
removal  of  the  promotion  of  thyroid  on  the 
chromaffine  tissue,  then  hyperfunction  of  the 
chromaffine  tissue  is  not  so  completely  intense 
as  after  extirpation  of  the  pancreas  alone;  hence, 
there  is  a  probable  heightened  mobiHzation  of 
fat.  Hence,  Falta  gives  the  following  explana- 
tion: the  mobilization  of  fat  is  increased,  the 
destruction  of  fat  decreased,  by  the  removal  of 


I20 

thyroid,  and  a  very  slow  decrease  of  body  weight 
ensues,  and  in  these  circumstances  we  have  sugar 
from  fats  and  a  heightened  quotient  of  dextrose 
to  nitrogen. 

Relation  of  Internal  Secretion  to  the  Sym- 
pathetic and  Parasympathetic  System. — Loewi 
has  shown  by  removal  of  the  "pancreas  in 
dogs  that  dropping  adrenalin  into  the  eye  causes 
mydriasis.  It  would  seem  that  adrenalin  in 
small  doses  does  not  act  upon  the  normal  eye, 
for  the  pancreas  has  an  inhibitory  effect  upon  the 
sympathetic  nervous  system.  When  the  pan- 
creas was  removed  the  sympathetic  became 
more  excitable  and  adrenalin  now  acts,  when 
normally  it  did  not.  In  human  diabetes  the 
adrenalin   action   on   the   pupil  is  inconstant. 

In  hyperthyroidism  by  continued  use  of  thyroid 
extract  there  seems  to  be  an  excitation  of  the 
sympathetic,  as  exophthalmos,  tachycardia, 
tremor,    sweat,    and    vaso-motor    disturbances. 

If  a  normal  dog  has  thyroid  extract  fed  to 
him,  then  adrenalin  acts  upon  the  pupil.  It 
has  been  shown  that  in  the  normal  thyroidless  dogs 
continued  use  of  thyroid  made  them  susceptible 
to  the  action  of  adrenalin  upon  the  pupil.  Here 
the  thyroid  increased  the  activity  of  the  sym- 
pathetic nervous  system. 

lodothyrin  also  heightens  the  excitability 
of  the  sympathetic  and  adrenalin  then  acts 
upon  the  normal  pupil.  In  about  20  cases  of 
Basedow's  disease  the  action  of  adrenalin  only 
dilated  the  pupil  in  4  cases. 


121 

Hyperthyroidism  also  acts  upon  the  para- 
sympathetic as  an  excitant,  as  is  shown  in  the 
well  known  antagonism  between  thyroid  extract 
and  atropin. 

Athyreoidism  conduces  to  lessened  excitability 
of  the  sympathetic,  for  removal  of  the  thyroid 
prevents  the  pressor  action  of  small  doses  of 
adrenalin. 

In  thyroidless  dogs  Asber  found  that  atropin 
acted  more  intensely  than  in  normal,  the  sphincter 
is  more  easily  paralyzed,  since  the  excitation 
state  of  the  parasympathetic  fibers  of  the  oculo 
motor  is  reduced.  In  thyroidless  dogs  pilocarpin 
has  a  diminished  activity. 

In  myxedema,  or  hypothyroidism,  we  have 
a  slow  circulation,  trophic  disturbances  and, 
perhaps,  the  slowness  of  the  intestinal  move- 
ments. 

While  adrenalin  governs  the  sympathetic, 
Falta  thinks  the  pancreas  secretion  may  govern 
the  vagus  of  the  parasympathetic. 

If  the  internal  secretion  of  the  pancreas 
governs  the  vagus,  then  irritation  of  the  vagus 
must  produce  an  increased  production  of  the 
internal  secretion  of  the  pancreas,  a  hyper- 
function  of  the  pancreas,  while  a  paralysis  of 
the  vagus  is  attended  with  a  decrease  of  the 
pancreatic  secretion.  Suitable  doses  of  pilo- 
carpin prevents  adrenalin  glycosuria. 

In  thyroidless  dogs  where  we  have  a  hyper- 
function  of  the  pancreas,  atropin  diminishes  this, 
and  adrenalin  again  produces  glycosuria. 


122 

Action  in  Metabolism. — In  these  statements 
I  shall  rely  mainly  upon  Falta^  who  has  made 
experiments  upon  this  subject.  In  the  state 
of  hunger,  thyreoidin,  adrenalin  and  infundib- 
ulin  increase  proteid  metabolism.  Pancreas 
and  parathyroid  inhibit  proteid  metabolism,  as 
their  removal  increases  it.  As  to  carbohydrates, 
adrenalin  and  infundibulin  increase  their  met- 
abolism;   pancreas  and  parathyroid    inhibit    it. 

Thyreoidin  accelerates  fat  metabolism ;  pancreas 
inhibits  it. 

Ingestion  of  thyroid  tablets  is  followed  by 
increased  excretion  by  the  intestine  of  phos- 
phates ;  with  the  ingestion  of .  the  hypophysis 
a  decrease  of  phosphates  in  urine  and  an  increase 
of  them  in  the  fecal  matter  ensues. 

Thyreoidin  and  infundibulin  increase  the  ex- 
cretion of  calcium  by  the  intestine  and  of 
magnesium  by  the  urine.  Osiris  has  shown 
that  the  excretion  of  phosphorus  by  the  kidneys 
and  intestines  is  exclusively  dependent  upon 
the  calcium  metabolism,  hence  thyreoidin  in- 
creases the  excretion  of  phosphorus.  After 
the  use  of  adrenalin  the  quotient  N  :  PvOg  falls. 

The  parathyroids  inhibit  calcium  excretion? 

The  chromaflfine  system  has  an  especial  affinity 
for  metabolic  changes  in  the  tissues  which  are 
rich  in  phosphorus  and  alkalies,  while  the  pan- 
creas protects  them. 

Feeding  adrenalin  to  animals  causes  the  ratio 
of  nitrogen  to  phosphorus  pentoxid  to  decrease 

1  Wiener  Klinische  Wochenschrift,   1909,  pp.   1059-1062. 


123 

while  the  calcium  and  sodium  excreted  is  in- 
creased. Removal  of  pancreas  and  parathyroids 
markedly  increases  the  excretion  of  chlorine 
in  the  urine  during  the  state  of  hunger. 

Infundibulin  increases  the  excretion  of  uric 
acid.  Here  the  increase  of  uric  acid  is  due  to 
oxidation  of  allantoin.  Adrenalin  increases  the 
excretion  of  both  uric  acid  and  allantoin. 

The  continuous  use  of  thyreoidin  produces 
no  atheroma  of  the  arterial  walls,  while  adrenalin 
and  infundibulin  cause  it.  In  thyroidectomized 
dogs,  infundibulin  has  less  action  on  proteid 
metabolism.  According  to  Diesing  the  pituitary 
contains  a  peculiar  organic  combination  of 
phosphorus,  the  thyroid  iodine,  the  spleen  iron, 
the  thymus  arsenic,  and  the  adrenals  sulphur. 
These  glands  regulate  the  supply  of  these  con- 
stituents in  the  blood  for  the  acts  of  metabolism. 

Secretion  and  Excretion. — In  conjunction  with 
Dr.  Saml.  B.  Harris  I  have  shown  that  adrenaUn 
is  excreted  in  small  amounts  by  the  kidney. 
The  urine  of  cats  who  had  received  adrenalin 
a  few  hours  previously  was  injected  into  jugular 
and  a  rise  of  arterial  tension  ensued.  Normally 
the  urine  of  the  cat  depresses  the  blood  pressure. 
Dale  has  shown  that  pituitary  is  also  excreted 
by  the  urine,  as  the  urine  of  the  cat  after  injection 
of  the  pituitary  had  a  pressor  action  when 
tested  on  another  cat. 

Pemberton  and  Sweet  have  shown  that  the 
adrenals  and  pituitary  inhibit  the  activity  of 
the   pancreatic   secretion.     This   is   not   due   to 


124 

vaso-constriction  in  the  gland  vessels,  as  Ed- 
munds held,  but  is  independent  of  the  systemic 
blood  pressure.  This  action  persists  when  the 
blood  pressure  is  below  normal.  This  inhibition 
by  the  pituitar}^  and  suprarenals  ensues  when  the 
pancreas  is  stimulated  by  the  action  of  hydro- 
chloric  acid   in   the   duodenum.^ 

Parchtner,  in  a  castrated  male  calf  1 1  months 
old,  found  a  diminution  of  oxygen  taken  into  the 
system  from  12  to  15  per  cent.  He  confirms 
Loewy  and  Richter's  results.^ 

In  castrated  female  dogs  Loewy  and  Richter 
found  that  ovarian  feeding  elevated  the  amount 
of  oxygen  taken  into  the  system  by  the  lungs 
even  above  normal.  Even  in  male  castrated 
dogs  oophorin  increased  the  oxygen  used  up 
above  normal,  while  in  the  non-castrate  oophorin 
showed  no  increased  using  up  of  oxygen  by  the 
animal.  In  young  animals  castration  causes  a 
slow  ossification  and  a  slow  calcification  com- 
pared with  non-castrates.  In  two  cases  of 
osteomalacia  before  castration  there  was  a 
deficiency  of  0.39,  comparing  the  CaO  ingested 
with  the  CaO  excreted.  After  castration  there 
was  an  excess  of  calcium  -t-5.78  retained,  com- 
paring the  calcium  ingested  with  the  calcium 
egested  (Gold th wait.  Painter,  Osgood  and  Mac- 
Crudden^). 

In  a  fat  person  Steyrer  has  showTi  in  thyroid- 

•  Archives  of  Internal  Med.,  Vol.  5,  No.  5,  p.  466. 
-  Oppenheim's  Handbuch  Biochemie,     Band    4,    2     Halfte    p. 
201. 

3  Ibid.,  p.  206. 


125 


feeding  that  there  was  a  fall  of  weight — the 
nitrogenized  substances  were  spared  but  the  fats 
were  used  up  causing  a  minus  balance  of  C, 
compared  with  carbon  ingested.^ 

Secretory  Nerves  in  the  Thyroid. — Asher  and 
Flack^  have  shown  that  on  irritating  the  superior 
laryngeal  nerve  which  dilates  the  blood  vessels 
of  the  thyroid  that  there  was  an  increased 
secretion  of  some  substance  by  the  thyroid  which 
augments  the  excitability  of  the  nervus  depressor. 
During  the  irritation  of  the  laryngeal  nerves 
by  electricity,  the  same  dose  of  adrenalin  elevates 
the  blood  pressure  more  if  the  depressors  have 
been  ligated  previously.  Von  Cyon  stated  that 
iodothyrin  excited  the  nervus  depressor.  Falta, 
by  metabolism  experiments,  has  shown  that  the 
adrenals  and  thyroid  assist  each  other  by  their 
respective  secretions. 

I  have  indicated  in  the  following  table  a 
provisional  relation  of  some  of  the  glands  with 
an  internal  secretion  upon  each  other. 


Thymus 

Thyroid 

Pars  anterior 

Hypophysis 

O 

Hypophysis 

O 

HH 

o      > 

o 

3 

5^ 

k 

> 

>— 1 

^        3 

'S 

5* 

n 

0'_ 

n 

ition 
> 

CO 

o    i 

' 

> 

bition 

> 

■-1 

^ 

^ 

Testis 

Hypophysis 

Testis  Ovary 

Parathyroid 

Pig.  19. 

1  Oppenheim's  Handbuch  Biochemie,  Band  4,  2  Halfte,  p.  234. 

2  Zentralblait  fiir  Physiologie  Band,  XXIV,  No.  6,  p.  211. 


126 


Pathology. 

Deficiency  of  parathyroid  secretion  produces 
tetany. 

Excess  of  secretion  by  thyroid  produces 
Basedow's  disease. 

Deficiency  of  thyroid  secretion  produces  in 
child   cretinism,   in   adult   myxedema. 

Parhon^  gives  the  following  parallel  of  symp- 
toms between  Basedow's  disease  and  mxye- 
dema. 


Basedow's  disease. 

Frequent  hypertrophy  of 
thyroid  gland. 

Excess  of  sudorific  secre- 
tion, skin  smooth  and 
moist. 

Electric  resistance  dimin- 
ished. 

Sensation  of  heat,  quite 
painful. 

Temperature  of  body  fre- 
quently   above    normal. 

Diarrhea      frequent. 

Nutritive  exchanges  fre- 
quently  exaggerated. 

Growth   accelerated. 

Enchondral  ossification  pre- 
cocious. 

Irritability  increased,  psy- 
chic lability. 

Emotional  instability. 


Myxedema. 

Absence  or  frequent 
atrophy  of   thyroid. 

Deficiency  of  sudorific 
secretion,  skin  dry,  after- 
wards wrinkled. 

Electric  resistance  in- 
creased. 

Continual  sensation  of 
cold. 

Temperature  of  the  body 
below  normal. 

Constipation  frequent. 

Nutritive  exchanges  dimin- 
ished. 

Growth  slow. 

Enchondral  ossification 

retarded. 

Psychic  apathy. 


Henry   J.    Berkeley^   has  found  that  patients 


1  Les  Secretions  Internes,  1909. 

^  Folia  Neuro-hiologica,  Nov.,  1908,  p.  157. 


127 

with  katatonia  have  their  mental  integrity- 
restored  by  partial  thyroidectomy. 

In  Basedow's  disease,  we  have  increased 
destruction  of  proteid.  This  augmented  met- 
abolism of  proteid  can  be  reduced  to  normal 
by  large  doses  of  carbohydrates  and  fats  for 
some  time.  Carbohydrates  and  fats  in  the  nor- 
mal man  reduces  the  metabolism  of  proteid. 

In  Basedow's  disease,  by  giving  large  doses 
of  sugar  we  can  produce  alimentary  glycosuria. 
Quite  often  we  have  Basedow's  disease  and 
glycosuria  combined.  By  the  use  of  thyroid 
tablets  we  have  occasional  diabetes,  probably 
due  to  a  latent  disposition  to  diabetes. 

Diabetes  can  ensue  from  hyperfunction  of 
thyroid,  or  excessive  action  of  adrenaUn.  In 
some  severe  cases  of  diabetes  in  the  young  the 
thyroid  could  not  be  felt.  Falta  found  in  dogs 
with  the  thyroid  and  pancreas  removed  a  strong 
diabetes.  It  is  well  known  that  disease  of  pan- 
creas produces  diabetes. 

The  diabetes  which  ensues  during  pregnancy 
in  nervous  cases  and  ends  after  deUvery  is  very 
probably  due  to  hyperhypophysy.  The  pro- 
motion of  activity  of  the  chromaffine  tissue 
by  the  thyroid  also  is  contributory. 

Tumors  of  adrenals  have  been  observed  by 
Grawitz  to  produce  diabetes,  perhaps  due  to 
hyperactivity  of  the  adrenals. 

Deficiency  of  adrenalin  produces  Addison's 
disease. 


128 


Hyperhypophysy  produces  in  the  child  giant- 
ism, in  the  adult  acromegaly. 

Hypohypophysy  produces  dwarfs  and  in- 
fantilism. 

Gross  lesions  of  the  pituitary  have  been  found 
in    at   least   four    cases   of   adiposis   dolorosa. 

If  ovarian  insufficiency  or  thyroid  insufficiency 
supervene  before  hyperhypophysy,  then  we  have 
Dercum's  disease. 

Delille^  makes  the  following  symptoms  for 
diseases  of  the  hypophysis: 


Hypohypophysy. 
Hypotension 
Tachycardia 

Painful   sensations  of   heat 
Diminished      quantity      of 

urine 
Anorexia 

Asthenia 

Nutrition  changes,  emacia- 
tion, in  certain  cases 
obesity 

Trophic  troubles 

Psychic  troubles 

Insomnia 

Mental  and  physical  back- 
wardness 

Less  resistance  to  infec- 
tions 

Signs  of  special  intracranial 
compression  by  a  tumor 
of  pituitary 

»  L'Hjpophyse,  1909. 


Hyperhypophysy. 
Hypertension 
Polyuria 
Glycosuria 
Emaciation 

Obesity     by     an     indirect 

action 
Red    blood    corpuscles, 

normal  or  above  normal 
Acromegaly 


Giantism 
Psychic  troubles 
Sleepiness 

Nearly  always     genital  in- 
sufficiency 
Frequent     hypothjToidism 

Signs  of  special  intra- 
cranial compression  by 
a    tumor   of    pituitary 


129 

Striimpell  thinks  sclerodermia  is  due  to  hy- 
pohypophysy.  Lafond  confirms  it.  Leman  and 
Van  Wart  suggest  a  hyperhy^ophysy  and  hy- 
pohypophysy  of  the  anterior  and  posterior 
part  of  the  pituitary,  making  thus  four  classi- 
fications  of  disease  in  this   part. 

Therapeutics. 

In  deficiency  or  loss  of  an  internal  secretion 
we  substitute  by  giving  the  gland  by  the  mouth. 
In  excessive  internal  secretion  of  a  gland  we 
can  overcome  it  by  its  antagonizing  gland. 

Bell  and  Schober  have  used  the  extract  of 
the  mammary  gland  in  uterine  myoma  and 
obtained  a  diminution  of  the  tumor  and  a  cessa- 
tion of  the  hemorrhages. 

Mykertschianz^  found  mammin  (Poehl),  an 
extract  of  the  mammary  gland  cause  the 
disappearance  of  uterine  fibroma  in  2  cases 
a  diminution  of  fibromas  in  21  cases,  and  no 
action  in  3  cases.  The  hemorrhage  and  pain 
were  diminished.  He  also  found  mammin  use- 
ful in  chronic  metritis. 

The  thyroid  has  been  used  to  restrain  metror- 
rhagia. It  cures  cretinism  and  myxedema. 
It  also  relieves  obesity  of  pale  people  but  not 
those  with  a  high  color. 

Osteomalacia  has  been  cured  in  many  cases 
by  ovarian  castration. 

Adrenalin  has  been  locally  applied  to  stop 
hemorrhages  by  its  local  vaso-constriction.     It 

'  Meunchener  Med.  Woch.,  Aug.  9,  1910,  p.  1705. 


I30 

has  also  been  used  in  congestions  of  the  con- 
junctiva and  of  the  nasal  mucous  membrane. 
It  has  been  used  in  asthmas  of  cardiac  and 
renal  origin  with  good  eflfect.  Here  the  vaso- 
dilation of  the  coronary  arteries  and  its  tonic 
action  on  the  cardiac  muscle  may  come  into  play. 

In  bronchial  asthma  it  has  been  applied  locally 
to  the  nasal  mucous  membrane,  and  given 
internally.  Internally  it  may  act  upon  the 
broncho-constrictor  muscles  of  the  bronchi  as 
an  inhibitor,  or  as  a  stimulant  upon  the  broncho- 
dilators,  or  if  there  is  congestion  of  the  bronchial 
mucous  membrane  in  these  cases  it  would  reduce 
the  congestion. 

It  has  been  found  after  the  removal  of  fluids 
from  the  pleural  or  peritoneal  cavities  that 
injection  of  adrenalin  prevents  its  reaccumulation. 
In  pneumonia  of  adults  and  children  it  has  been 
used  to  prevent  the  debility  of  the  muscular 
structure  of  the  heart.  In  these  cases  it  raises 
the  peripheral  resistance  by  the  vaso-constric- 
tion  and  makes  the  left  ventricle  produce  more 
work.  Pulmonary  edema  in  these  states  is 
not  produced  by  its  use. 

In  Addison's  disease  it  improves  but  does  not 
cure,  as  usually  the  lesions  are  of  an  incurable 
nature,  being  either  tubercular  or  malignant. 
Used  by  the  mouth  in  the  lower  animals  in  large 
doses  it  causes  no  perceptible  increase  of.  blood 
pressure.  The  surest  way  to  its  activity  is  sub- 
cutaneously,  intramuscularly  and  intravenously. 
Adrenalin  in  patients  with  arterio-sclerosis  and 


131 

high  blood  pressure  must  be  used  with  great  care. 
Wiggers^   has   studied   the   effect   upon  internal 
hemorrhages,  and  has  arrived  at  the  conclusion 
that  adrenalin  increases  the  quantity  of  blood 
in  the  pulmonary  veins  as  well  as  in  the  arteries, 
and    that    its    use    in    pulmonary    hemorrhage 
can  not    be  looked    upon  as    favorable.     Small 
doses  of  adrenalin,   according  to  Wiggers,   that 
do  not  slow  the  heart  generally  cause  no  rise 
of    pulmonary    venous    and    arterial    pressure, 
or  only  a  feeble  rise,  even  though  the  systemic 
pressure    rises    appreciably.     Pressure    measure- 
ments,    however,     give    no     accurate    estimate 
of  the  blood  contents  of  these  vessels,  for  out- 
flow records  show  that  this  is  decidedly  increased 
by  adrenalin.     This  increase  is  not  due,  according 
to  Wiggers,  to  a  "back  effect"  from  the  systemic 
rise,   for   the   pressure  in   the  left   auricle  falls. 
It  is  not  due  to  constriction  of  the  pulmonary 
vessels,    for    the    venous    pressure    should    then 
fall  and  not  rise.     It  is  probably  due  to  the  fact 
that  the  total  volume  of  blood  thrown  out  by 
the  augmented  contraction  of  the  right  ventricle 
is  not  entirely  forced   ahead   to   be  utilized  in 
the  feeding  of  the  left  heart,  but  instead  is  stored 
in    the    distensible    pulmonary    veins.     Wiggers 
advises  in  intestinal  hemorrhages  not  large  doses, 
but  small  ones,   0.025    milligram,   his    so-called 
"therapeutic   doses,"    which   produce   a    rise   of 
blood  pressure  and  a  diminished  bleeding  from 
the   intestinal   vessels.     In   these   cases    a   high 

'  Archives  of  Internal  Medicine,  May,  1909. 


132 

blood  pressure  should  be  avoided  by  a  study 
of  the  rise  by  the  spygmomanometer  during 
the  injections.  In  1897,  I  showed  that  the 
adrenalin  relaxed  the  intestine,  which  conduces 
to   a   checking  of  intestinal  hemorrhage. 

Heidenhain^  found,  as  others  have,  that  adren- 
alin in  cases  of  collapse  from  weakness  of  the  vaso- 
motor center  in  pneumonia,  diphtheria  and 
peritonitis  gave  good  results.  It  must  be 
given  subcutaneously  or  by  the  vein  diluted 
with  salt  solution.  He  also  used  it  in  an  ap- 
parently moribund  case  to  tide  him  over  an 
operation  for  ileus. 

Kownatzki  cured  a  patient  afflicted  with 
osteomalacia  by  adrenalin.^ 

I  have  referred  to  W.  N.  Berkeley's  treatment 
of    paralysis    agitans    by    parathyroid    extract. 

Parhon  and  Urechia  have  tried  the  pituitary 
gland  in  paralysis  agitans  and  have  seen  certain 
symptoms  disappear,  such  as  low  arterial  tension, 
tachycardia,  the  sensation  of  heat,  increased 
perspiration,  insomnia,  and  a  diminution  of 
the  trembling.  However,  the  rigidity  was  not 
modified. 

Dr.  A.  F.  Jaugeas  has  had  good  results  from 
the  X-rays,  in  tumors  of  the  hypophysis  and 
thinks  they  should  be  tried  before  any  surgical 
operation  is  attempted. 

Corpus    luteum. — Maits^    concludes    from    the 

^  Jourtial  Am.  Med.  Association,  p.  2100. 

2  Berlin  Klin.  Wochenschrift,  No.  31.  p.  1469. 

3  University    of    Penna.    Medical    Bulletin,    Vol.    XXIII,   Nos. 
5  and  6,  p.  275. 


133 

use  of  the  extract  of  human  corpus  luteum  that 
it  has  a  distinct  therapeutic  action  in  osteomalacia 
in  disturbances  of  the  natural  and  artificial 
menopause  and  in  hypofunction,  due  to  infantile 
uterus. 

Antidote. — Falta  and  IvCovic^  thought  adren- 
alin was  an  antidote  to  strychnia,  but  Hans 
Januschke,^  in  repeating  the  experiments  of  Falta 
and  Ivcovie,  arrived  at  the  following  results: 

(i)  Adrenalin  is  not  able  to  prevent  the 
poisonous  action  of  strychnia  on  the  nervous 
system  of  the  frog. 

(2)  Such  adrenalin  and  strychnia  mixtures 
which  remain  non-toxic  by  subcutaneous  use 
in  guinea  pigs  show  typical  strychnia  poisoning 
by  the  intravenous  use.  The  view  of  A.  Exner, 
Meltzer  and  Auer,  that  there  is  a  delay  in  the 
absorption  of  the  poison  in  the  lymphatics, 
receives  support  in  his  experiments. 

(3)  That  the  diastolic  arrest  of  the  frog's 
heart  by  strychnia  can  be  caused  to  beat  by 
adrenalin.  This  is  not  specific  action  but  only 
an  irritant  action.  Similar  results  can  be  pro- 
duced by  camphor,  barium,  strophanthin  and 
atropin,  also  by  mechanical* and  electrical  irrita- 
tion. 

Olds^  finds  that  thyroidectomized  rats  show 
the  same  resistance  to  morphine-poisoning 
as  normal  rats.  He  does  not  confirm  Reid 
Hunt's  results. 

1  Berlin  Klin.  Wockenschrifi,    1909,  p.  1929. 

2  Wiener  Klinische  Wochenschrift,   1910.  p.  284. 

3  Am.  Journal  of  Physiology,  Vol.  XXVI.  p.  360.  . 


O.^ 


